6-heterocyclic-4-amino-1,3,4,5,-tetrahydrobenz [cd]indoles

ABSTRACT

6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz-[cd]indoles are provided which are useful in modifying the function of serotonin in mammals.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of application Ser.No. 08/299,175, filed Aug. 31, 1994; which is a divisional applicationof application Ser. No. 07/954,105, filed Sep. 30, 1992, now U.S. Pat.No. 5,364,856; which is a continuation-in-part application ofapplication Ser. No. 07/677,016 filed Mar. 28, 1991, now U.S. Pat. No.5,244,912.

FIELD OF THE INVENTION

This invention relates to6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[cd]indoles and their usein modifying the function of serotonin in a mammal.

BACKGROUND OF THE INVENTION

Flaugh in U.S. Pat. No. 4,576,959 (issued 1986) disclosed a family of6-substituted-4-dialkylamino-1,3,4,5-tetrahydrobenz[cd]indoles which aredescribed as central serotonin agonists. Leander in U.S. Pat. No.4,745,126 (1988) disclosed a method for treating anxiety in humansemploying a 4-substituted-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxamidederivative.

European Patent Application 399,982 discloses certainheterocyclic-substituted aminotetralins. These compounds are disclosedas being serotonin agonists, partial agonists or antagonists.

It has now been found that certain 6-heterocyclic-substitutedtetrahydrobenz[cd]indoles are useful in treating conditions requiringmodification of the serotonin function in the body.

SUMMARY OF THE INVENTION

This invention relates to compounds of the Formula 1 ##STR1## wherein:

R¹ is hydrogen, C₁ -C₄ alkyl, C₃ -C₄ alkenyl, cyclopropylmethyl, aryl(C₁ -C₄ alkyl), --(CH₂)_(n) S(C₁ -C₄ alkyl), --C(O)R⁴, or --(CH₂)_(n)C(O)NR⁵ R⁶ ;

R² is hydrogen, C₁ -C₄ alkyl, cyclopropylmethyl or C₃ -C₄ alkenyl;

R³ is hydrogen, C₁ -C₄ alkyl or an amino-blocking group;

n is 1-4;

R⁴ is hydrogen, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy or phenyl;

R⁵ and R⁶ are independently hydrogen, C₁ -C₄ alkyl, or C₅ -C₈cycloalkyl, with the proviso that when one of R⁵ or R⁶ is a cycloalkylthe other is hydrogen;

HET is a tetrazolyl ring, a substituted tetrazolyl ring or an aromatic5- or 6-membered heterocyclic ring, said ring having from one to threeheteroatoms which are the same or different and which are selected fromthe group consisting of sulfur, oxygen, and nitrogen with the provisothat the 6-membered heterocyclic ring can only contain carbon andnitrogen and with the further proviso that a 5-membered ring may containno more than one oxygen or one sulfur but not both oxygen and sulfur.

The invention also provides a pharmaceutical formulation comprising acompound of Formula 1 in combination with a pharmaceutically acceptableexcipient therefor.

A further embodiment of the invention is a method for effecting abiological response at the 5HT_(1A) or 5HT_(1D) receptor byadministering a compound of Formula 1. Another embodiment involves amethod for treating a variety of conditions in a mammal which requireregulation of serotonin functions by administering a compound of Formula1.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" represents a straight or branched alkylchain having the indicated number of carbon atoms. For example, "C₁ -C₄alkyl" groups are methyl, ethyl, n-propyl, isopropyl, n-butyl,sec.-butyl, isobutyl and tert-butyl. "C₁ -C₈ alkyl" groups include thoselisted for C₁ -C₄ alkyl as well as n-pentyl, 2-methylbutyl,3-methylbutyl, n-hexyl, 4-methylpentyl, n-heptyl, 3-ethylpentyl,2-methylhexyl, 2,3-dimethylpentyl, 5-octyl, 3-propylpentyl,6-methylheptyl, and the like.

The term "C₃ -C₄ alkenyl" refers to olefinically unsaturated alkylgroups such as --CH₂ CH═CH₂, --CH₂ CH₂ CH═CH₂, --CH(CH₃)CH═CH₂ and thelike.

The term "aryl" means an aromatic carbocyclic structure having six toten carbon atoms. Examples of such ring structures are phenyl, naphthyl,and the like.

The term "cycloalkyl" means an aliphatic carbocyclic structure havingthe indicated number of carbon atoms in the ring. For example, the term"C₃ -C₇ cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

The term "aryl (C₁ -C₄ alkyl)" means an aryl structure joined to a C₁-C₄ alkyl group. Examples of such groups are benzyl, phenylethyl,α-methylbenzyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl,4-phenylbutyl, and the like. Similarly the term "aryl (C₁ -C₃ alkyl)"means an aromatic carbocyclic structure joined to a C₁ -C₃ alkyl.

The C₁ -C₈ alkyl, aryl, aryl (C₁ -C₄ alkyl) and aryl (C₁ -C₃ alkyl)groups can be substituted by one or two moieties. Typical aryl and/oralkyl substitutents are C₁ -C₃ alkoxy, halo, hydroxy, C₁ -C₃ thioalkyl,nitro, and the like. Moreover, the aryl, aryl (C₁ -C₄ alkyl) and aryl(C₁ -C₃ alkyl) groups can also be substituted by a C₁ -C₃ alkyl or atrifluoromethyl group.

In the foregoing, the term "C₁ -C₃ alkyl" means any of methyl, ethyl,n-propyl, and isopropyl; the term "C₁ -C₃ alkoxy" means any of methoxy,ethoxy, n-propoxy, and isopropoxy; the term "halo" means any of fluoro,chloro, bromo, and iodo; and the term "C₁ -C₃ thioalkyl" means any ofmethylthio, ethylthio, n-propylthio, and isopropylthio.

Examples of substituted C₁ -C₈ alkyl are methoxymethyl, trifluoromethyl,6-chlorohexyl, 2-bromopropyl, 2-ethoxy-4-iodobutyl, 3-hydroxypentyl,methylthiomethyl, and the like.

Examples of substituted aryl are p-bromophenyl, m-iodophenyl, p-tolyl,o-hydroxyphenyl, β-(4-hydroxy)-naphthyl, p-(methylthio)phenyl,m-trifluoromethylphenyl, 2-chloro-4-methoxyphenyl, α-(5-chloro)naphthyl,and the like.

Examples of substituted aryl (C₁ -C₄ alkyl) are p-chlorobenzyl,o-methoxybenzyl, m-(methylthio)-α-methylbenzyl,3-(4'-trifluoromethylphenyl)propyl, o-iodobenzyl, p-methylbenzyl, andthe like.

The term "amino-blocking group" is used herein as it is frequently usedin synthetic organic chemistry, to refer to a group which will preventan amino group from participating in a reaction carried out on someother functional group of the molecule, but which can be removed fromthe amine when it is desired to do so. Such groups are discussed by T.W. Greene in chapter 7 of Protective Groups in Organic Synthesis JohnWiley and Sons, New York, 1981, and by J. W. Barton in chapter 2 ofProtective Groups in Organic Chemistry J. F. W. McOmie, ed., PlenumPress, New York, 1973, which are incorporated herein by reference intheir entirety. Examples of such groups include benzyl and substitutedbenzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl;those of the formula --COOR where R includes such groups as methyl,ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl,isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl,o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acylsuch as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl,trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such asmethanesulfonyl, p-toluenesulfonyl, p-bromobenzene-sulfonyl,p-nitrophenylethyl, and p-toluenesulfonyl-aminocarbonyl. Preferredamino-blocking groups are benzyl (--CH₂ C₆ H₅), acyl [C(O)R] or SiR₃where R is C₁ -C₄ alkyl, halomethyl, or 2-halo-substituted-(C₂ -C₄alkoxy).

The term "aromatic 5- or 6-membered heterocyclic ring" refers to a ringcontaining from one to three heteroatoms which can be nitrogen, oxygenor sulfur. The 5-membered heterocyclic rings can contain carbon andnitrogen atoms and up to one oxygen or one sulfur but not one of each.In 5-membered rings not containing oxygen or sulfur, one nitrogen can besubstituted with either a hydrogen, C₁ -C₃ alkyl, phenyl or (C₁ -C₃alkyl)phenyl group. The 6-membered heterocyclic rings can contain carbonand nitrogen atoms only. The 5- or 6-membered rings can have one or twoof the carbon atoms in the ring substituted independently with C₁ -C₃alkyl, halogen, OH, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, NH₂, CN or phenyl.Adjacent carbons in the heterocyclic ring may be connected with a--CH═CH--CH═CH-- bridge to form a benzo-fused ring on the heterocycle.

These aromatic 5- or 6-membered heterocyclic rings can be eithersubstituted or unsubstituted and include furan, thiophene, thiazole,oxazole, isoxazole, isothiazole, oxadiazole, thiadiazole, pyridine,pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, andtriazole. The heterocyclic ring can be attached to the benzene ring byany carbon in the heterocyclic ring, for example, 2- or 3-furan.

The term "substituted tetrazolyl ring" refers to a tetrazolyl ringsystem which has a C₁ -C₃ alkyl or phenyl substituent on the 2-positionnitrogen atom of such ring system.

As used herein the following terms refer to the structure indicated andinclude all of the structural isomers: ##STR2##

While all of the compounds of the invention are useful for the purposestaught herein, certain of the present compounds are preferred for suchuses. Preferably R¹ and R² are both C₁ -C₄ alkyl, particularly n-propyl,R³ is hydrogen, and HET is one of the following isoxazole, oxazole,pyrazole, pyridine, thiazole, furan, thiophene or oxadiazole. Otherpreferred aspects of the present invention are noted hereinafter.##STR3##

The compounds of the instant invention have at least one chiral centerand therefore at least two stereoisomers can exist for each. A chiralcenter exists at position 4 of Formula 1. If a substitutent groupcontains a chiral center, then additional stereoisomers can exist.Racemic mixtures as well as the substantially pure stereoisomers ofFormula 1 are contemplated as within the scope of the present invention.By the term "substantially pure", it is meant that at least about 90mole percent, more preferably at least about 95 mole percent and mostpreferably at least 98 mole percent of the desired stereoisomer ispresent compared to other possible stereoisomers. Particularly preferredstereoisomers of Formula 1 are those in which the configuration of thechiral center at position 4 is R.

The terms "R" and "S" are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term"R" refers to "right" and refers that configuration of a chiral centerwith a clockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Theterm "S" or "left" refers to that configuration of a chiral center witha counterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (heaviest isotopefirst). A partial list of priorities and a discussion ofstereo-chemistry is contained in the book: The Vocabulary of OrganicChemistry Orchin, et al., John Wiley and Sons Inc., publishers, page126, which is incorporated herein by reference.

As set forth above, this invention includes the pharmaceuticallyacceptable salts of the compounds of Formula 1. Since the compounds ofthis invention are amines, they are basic in nature and accordinglyreact with any number of inorganic and organic acids to formpharmaceutically acceptable salts using acids such as hydrochloric acid,nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid,hydroiodic acid, phosphorous acid and others, as well as salts derivedfrom nontoxic organic acids such as aliphatic mono and dicarboxylicacids, amino acids, phenyl-substituted alkanoic acids, hydroxyalkanoicand hydroxyalkandioic acids, aromatic acids, aliphatic and aromaticsulfonic acids. Such pharmaceutically acceptable salts thus includesulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,caprylate, acrylate, formate, tartrate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate,hexyne-1,6-dioate, hippurate, benzoate, chlorobenzoate, methylbenzoate,phthalate, terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, malate, naphthalene-1-sulfonate, naphthalene-2-sulfonate andmesylate.

Preferred compounds of Formula 1 include the compounds in which R³ ishydrogen, R¹ and R² are both either n-propyl or methyl and HET is3-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 5-oxazolyl, 3-isothiazolyl,5-isothiazolyl, 2-imidazolyl or 4-imidazolyl. These compounds includethe stereoisomers at position 4, i.e., racemic mixture of 4-R and 4-S aswell as the substantially pure stereoisomers of each in which theconfiguration at postion 4 is R or S. Compounds having 4Sstereochemistry are particularly preferred.

As depicted in Scheme I, the compounds of the present invention can beprepared by reacting a 4-amino-6-metallo-substitutedtetrahydrobenz[cd]indole as represented by structure 2 with aheterocyclic compound represented by structure 4 . In structure 2, Mrepresents a metallo moiety such as lithium, magnesium, zinc, tin,mercury, boronic acid (--BO₂ H₂) and the like while Z is anamino-blocking group. When the metallo moiety is multivalent, it isnormally associated with other moieties such as, for example, halo formagnesium (Grignard reagent) and alkyl groups for tin (trialkyltin). Theheterocycle represented by structure 4 contains a leaving group "L",such as a chloro, bromo, or trifluoromethylsulfonoxy group, which can bedisplaced by the metallo-indole. The heterocycle can be substituted asset forth hereinabove. Alternatively, a6-metallo-1,2,2a,3,4,5-hexahydrobenz[cd]indole 3 can be similarlyreacted with a heterocyclic 4 to provide the6-heteroaryl-1,2,2a,3,4,5-hexahydrobenz[cd]indole 5 which can then beoxidized and the blocking group Z exchanged or replaced to provide thecompounds of Formula 1 . ##STR4##

The reaction of the metallo-indole 2 or metallo-indoline 3 andheterocycle 4 is accomplished in the presence of a palladium or nickelcatalyst such as Pd[P(C₆ H₅)₃ ]₄, PdCl₂, Pd[P(C₆ H₅)₃ ]₂ Cl₂, Ni(acac)₂,NiCl₂ [P(C₆ H₅)₃ ]₂ and the like, wherein "acac" representsacetylacetonate and "C₆ H₅ " represents a phenyl group. Theorganometallic reagent 2 or 3 is prepared by methods commonly used inthe art for such preparations, for example, the lithium or magnesiumreagents can be prepared by contacting the appropriate 6-chloro-,6-bromo- or 6-iodo-substituted tetrahydro- or hexahydro- benzindole withan organolithium reagent or magnesium metal in a solvent such as etheror tetrahydrofuran. Other organometallic derivatives can be used such aszinc, tin, mercury or boronic acid (--BO₂ H₂). The zinc, tin and mercuryreagents can be prepared by reaction of the lithiated benzindole with azinc, tin or mercury derivative such as zinc chloride,chlorotrialkylstannane, or mercuric chloride. The boronic acidderivative can be prepared by reacting the lithium reagent withtrimethylborate followed by hydrolysis of the resulting boronate ester.Mercuric acetate can be contacted directly with the hexahydrobenzindoleto provide the mercurated derivative.

The 1-nitrogen of the benzindole is preferably protected with a groupsuch as triphenylmethyl (trityl), benzyl, or, for thetetrahydrobenzindole only, triisopropylsilyl. These protecting groupsare represented by Z in structures 2 and 3. The protecting group can beremoved after the coupling reaction is accomplished to provide the1-hydrobenzindole compound.

An alternative method of preparing the compounds of the instantinvention involves contacting an organometallic reagent prepared from aheterocyclic compound with a 6-bromo or 6-iodo-4-aminobenzindole. Thereaction is accomplished in the presence of a catalyst such as that usedin reaction Scheme I. The metal in the organometallic derivative of theheterocycle can be lithium, magnesium (Grignard reagent), zinc, tin,mercury, or a boronic acid (--BO₂ H₂). These organometallic compoundscan be prepared by standard methods, as described above for thebenzindoles. Alternatively, the lithiated heterocycles can be preparedby treating a heterocycle with a strong base such as an alkyllithium ora lithium dialkylamide.

Unless otherwise indicated, in the following preparation procedures,R_(a) and R_(a) ' may independently be hydrogen, C₁ -C₃ alkyl, halogen,OH, O(C₁ -C₃ alkyl), S(C₁ -C₃ alkyl), NH₂, CN, or phenyl. R_(b) may behydrogen, C₁ -C₃ alkyl, phenyl, or (C₁ -C₃ alkyl)phenyl. R_(c) may behydrogen or C₁ -C₃ alkyl. R_(d) may be OH, O(C₁ -C₃ alkyl), O(phenyl),O(C₁ -C₃ alkylphenyl), halo, S(C₁ -C₃ alkyl), S(phenyl), S(C₁ -C₃alkylphenyl), NH₂, NH(C₁ -C₃ alkyl), N(C₁ -C₃ alkyl)₂, OCO(C₁ -C₃alkyl), OCO(phenyl), OCO(C₁ -C₃ alkylphenyl) and the like.

In an alternative preparation procedure, compounds of the instantinvention having a 5-membered heterocyclic ring in the 6-position can beprepared by the cycloaddition of a compound of the type represented instructure 8 wherein R¹ and R² are as defined above and B is anamino-protecting group or hydrogen, ##STR5## with a 1,3-dipole of thetype ⁺ T=U-V⁻ in which T, U, and V can be selected from the followinglist of (a) through (i).

    ______________________________________                                        T               U           V                                                 ______________________________________                                        (a)     CR.sub.a    N           CHR.sub.a                                     (b)     CR.sub.a    N           NR.sub.b                                      (c)     CR.sub.a    N           O                                             (d)     N           N           O                                             (e)     CR.sub.a    CR.sub.a '  NR.sub.b                                      (f)     CR.sub.a    CR.sub.a '  O                                             (g)     N           CR.sub.a '  CHR.sub.a                                     (h)     N           CR.sub.a '  NR.sub.b                                      (i)     N           CR.sub.a '  O                                             ______________________________________                                    

In this list R_(a) and R_(a) ' are not OH or NH₂, N represents nitrogenand O represents oxygen. This cycloaddition provides products of thestructure 10, wherein R¹ and R² are as defined above and B is an aminoprotecting group or hydrogen. ##STR6## The 1-nitrogen of structures 8and 10 can be protected using standard protecting groups preferably (C₂H₅)₂ NC(O)--, triisopropylsilyl, or benzenesulfonyl.

Alternatively, the 6-alkyne-substituted indole of structure 8 can bereacted with a dipole of the type ⁺ T-U=V⁻ in which T, U, and V areselected from the following list for (j) and (k):

    ______________________________________                                               T          U          V                                                ______________________________________                                        (j)      CHR.sub.a    N          N                                            (k)      NR.sub.b     N          N                                            ______________________________________                                    

In this list R_(a) is not OH or NH₂ and N is nitrogen. This reactionprovides products of structure 12, ##STR7## wherein R¹, R², R_(a) and Bare as defined above

Alternative procedures for preparing certain of the instant compoundsare set forth hereinbelow in Schemes 1 through 19. As used in thesereaction Schemes, "At" refers to the benz[cd]indole, which can be1,3,4,5-tetrahydro or 1,2,2a,3,4,5-hexahydro, with the indicatedsubstituent in the 6-position, "Me" is methyl, "Et" is ethyl, "NBS"represents n-bromosuccinimide, R_(a), R_(b), R_(c) and R_(d) are definedabove, "MsCl" represents methanesulfonyl chloride, "Δ" represents heat,".o slashed." and "Ph" each represent phenyl, "DMF" representsdimethylformamide, "TMS" represents trimethylsilyl, "[O]" represents anoxidant, Lawesson's reagent is p-methoxyphenylthionophosphine sulfidedimer, "Ac" represents acetyl, "NCS" represents N-chlorosuccinimide,"DCC" represents dicyclohexylcarbodiimide, "DMS" represents dimethylsulfide, "Im" represents 1-imidazolyl, and "[H]" represents a reductant.As set forth hereinabove, the 1-nitrogen of the benz[cd]indole isnormally protected with an amino blocking group. When Ar istetrahydrobenz[cd]indole, the 1-blocking group is preferablytriisopropylsilyl. When Ar is hexahydrobenz[cd]indole, the prefered1-blocking group is triphenylmethyl. In the reaction schemes provided,Ar is preferably hexahydrobenz[cd]indole with the resulting6-heteroaryl-substituted hexahydrobenz[cd]indole being oxidized to thecorresponding tetrahydrobenz[cd]indole product. ##STR8## where R ishydrogen, C₁ -C₃ alkyl or phenyl

Scheme 20 illustrates a preparation of a starting material for reactionScheme 1. ##STR9##

In Scheme 20, epoxides of Formula 16 are known to the art or can beprepared from compounds known to the art using common reagents andtechniques. For example, Flaugh, et al., J. Med. Chem., 31, 1746 (1988);Nichols et al., Org. Prep. and Proc., Int., 9, 277 (1977); and Leanna etal., Tet. Lett., 30, No. 30, 3935 (1989), teach methods of preparationof various embodiments of compounds of structures 16. Those skilled inthe art of organic chemistry will recognize that there are fourstereoisomers of structure 16: ##STR10## Structures 16a and 16b areherein referred to collectively as the exo-isomers; similarly,structures 16c and 16d are the endo-isomers. Leanna et al., supra, teachthe preparation of epoxides of structures 16 which are substantially exoor substantially endo, as desired. The preferred starting material isthe compound of structure 16wherein Z is benzoyl and X is hydrogen; themost preferred starting material is the mixture of substantially theexo-isomers thereof.

Amino alcohols of structure 18 are formed by reacting an epoxide ofstructure 16 with an amine of formula R¹⁰ NH₂. Such amines are readilyavailable. Opening of the epoxide ring proceeds substantiallyregiospecifically with the amino group at the 5-position and thehydroxyl group at the 4-position. The reaction is also stereospecific inthe sense that stereoisomers of structure 18a-d are formed from,respectively, stereoisomers of structure 16a-d, ##STR11##

A stereoselective synthesis of the amino alcohol of structure 18, andhence of all the subsequent intermediates and products of Scheme 20, canbe effected by using a substantially pure enantiomer of an amine of theformula R¹⁰ NH₂ wherein R¹⁰ contains at least one chiral center. Thediastereomers of the resulting amino alcohol can then be separated by anumber of means known in the art, for example by chromatography orcrystallization. Suitable solvents for recrystallization include thosesuch as diethyl ether, n-butanol, and mixtures of hexane and ethylacetate. An alternative method of achieving a stereospecific synthesisis depicted in Scheme 20 and comprises conversion of all thediastereomers of structure 18 to corresponding diastereomers ofstructure 20, followed by the separation of said diastereomers ofstructure 20; that alternative method is discussed below. If astereoselective synthesis is not desired, then separation of thestereoisomers of the amino alcohol of structure 18 is not required andthe amine R10NH2 need not be optically active.

A particularly efficient stereoselective process for a highly preferredcompound of structure 18,1-benzoyl-4-hydroxy-5-(1-phenylethyl)amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole,comprises the reaction of a mixture of substantially the exo-isomers ofthe corresponding epoxide of structure 16, or a mixture of substantiallythe endo-isomers of the corresponding epoxide of structure 16, with asubstantially pure enantiomer of 1-phenethylamine in the solventn-butanol and the subsequent selective crystallization of one of the twoisomers of the amino alcohol. The temperature of the reaction can befrom about 50° to about 150° C., preferably about 80° to about 100° C.

After the reaction is complete, as determined for example by thin layerchromatography or liquid chromatography, the desired amino alcohol iscrystallized at about -20° to about 40° C.; the preferred temperaturefor the crystallization is about 0° to about 15° C. Therefore thisprocess has the valuable attribute that the reaction and the separationof stereoisomers occur efficiently in a single step. By the properselection of the epoxide isomers, exo or endo, and the enantiomer of1-phenylethylamine, R or S, one can determine which of the stereoisomersof the compound of structure 18precipitate from the reaction mixture.

A number of methods of forming aziridines such as those of structure 20from amino alcohols such as those of Formula 18 are known to the art.Two examples are the use of diethyl azodicarboxylate andtriphenylphosphine (0. Mitsunobu, Synthesis, January, 1981, page 1), andthe use of bromine and triphenyl-phosphine (J. P. Freemer and P. J.Mondron, Synthesis, December, 1974, page 894).

A particularly efficient alternative to the above methods involvestreating a compound of structure 18 with a tertiary amine in an inertsolvent followed by the addition of methanesulfonyl chloride. Thefollowing stereoisomers of the aziridine of structure 20, 20a-d, ariserespectively from the stereoisomers of structure 18a-d, with retentionof configuration at any chiral center in the substituents Z, R¹⁰ or X:##STR12## Suitable tertiary amines are those of the formula (R¹¹)₃ N,where the R¹¹ groups are independently C₁ -C₄ alkyl. Suitable solventsare chlorinated hydrocarbons such as methylene chloride, chloroform,carbon tetrachloride, and dichloroethane; aromatic hydrocarbons such asbenzene, toluene, and the xylenes; and ethers such as tetrahydrofuran,diethyl ether, and methyl t-butyl ether. The reaction can be conductedat a temperature from about -35° to about 45° C. In the preferredembodiment, the amino alcohol is treated with triethylamine in methylenechloride at about -20° to about 0° C., then the reaction mixture iswarmed to about 15° to about 35° C. for the completion of the reaction.If desired, the product, an aziridine of structure 20, can becrystallized from an appropriate solvent such as acetonitrile orisopropanol after an aqueous workup. In the event that Z contains atleast one chiral center in substantially a single stereoconfigurationand that the aziridine of structure 20 is prepared as a mixture ofstereoisomers, said stereoisomers can be separated by methods such aschromatography and crystallization, thereby providing a stereospecificsynthesis of the aziridine of structure 20 and subsequent products.

The aziridine ring can be opened to form an intermediate secondary amineof structure 22. A number of methods of opening aziridines are commonlyknown. It is, however, crucial that the method used for opening theaziridine to form a secondary amine of structure 22 be substantiallyregiospecific; the aziridine must be opened to form substantially the4-amino compound rather than the 5-amino compound. One such method iscatalytic hydrogenolysis as taught by Y. Sugi and S. Mitsui, Bull. Chem.Soc. Jap., 43, pp. 1489-1496 (1970). Catalysts which are suitable arethe usual hydrogenation and hydrogenolysis catalysts, such as the noblemetal catalysts; the preferred catalyst is palladium. Suitable solventsinclude hydrocarbons such as hexanes and heptanes; aromatic hydrocarbonssuch as benzene, toluene, xylenes, ethylbenzene, and t-butylbenzene;alcohols such as methanol, ethanol, and isopropanol; and mixtures ofsolvents such as acetic acid mixed with said alcohols. The preferredsolvent for preparing the compound of structure 22, wherein Z isbenzoyl, X is hydrogen, and R¹⁰ is 1-phenylethyl, is a mixture oftetrahydrofuran and phosphoric acid or acetic acid. The source ofhydrogen can be an atmosphere of elemental hydrogen supplied at apressure of about 1 atmosphere or higher, or the source of hydrogen canbe compounds which are suitable to serve as hydrogen donors in acatalytic transfer hydrogenolysis reaction, such as formic acid,hydrazine, or cyclohexene. The preferred hydrogen source is anatmosphere of hydrogen gas supplied at about 1 to about 10 atmospherespressure. The temperature of the reaction may be from about -20° toabout 80° C.; the preferred temperature for the hydrogenolysis of theaziridine wherein Z is benzoyl, X is hydrogen, and R¹⁰ is 1-phenylethylis about -20° to about 0° C.

The conversion of compounds of structure 20to compounds of structure 22proceeds without disturbing the stereochemical configuration of thechiral centers at the 2a- or 4-positions of the structure 22 or of thechiral centers that may be present in any of the substituents.

If desired, the compound of structure 22can be isolated by the usualmethods such as crystallization. The secondary amine of structure 22 canbe converted to a primary amine of structure 24 by a number of methodsknown to the art of organic chemistry, or alternatively the secondaryamine itself can be isolated.

However, the preferred method is to convert the secondary amine ofstructure 22 to the primary amine of structure 24without isolating thesecondary amine, but rather by simply continuing without interruptionthe hydrogenolysis reaction that produced the compound of structure 22.Therefore, the preferred solvent and catalyst are the same as those forthe preparation of the secondary amine of structure 22. It may bedesirable to conduct the hydrogenolysis of the secondary amine ofstructure 22 at a different temperature or a different pressure ordifferent temperature and pressure than the hydrogenolysis of theaziridine of structure 20. For the hydrogenolysis of the preferredcompound of structure 22 wherein Z is benzoyl, X is hydrogen, and R¹⁰ is1-phenylethyl, the preferred temperature and pressure are about 50° toabout 60° C. and about 1 to about 20 atmospheres. Under these conditionsthe hydrogenolysis of compounds of structure 22 to compounds ofstructure 24 proceeds without disturbing the stereochemicalconfiguration of the chiral center at the 4-position.

The isolation of the compound of structure 24 can be accomplished by theusual methods such as crystallization. If desired, the compound ofstructure 24 can be further purified, for example by recrystallization.

Of course, as those skilled in the art will recognize, variations ofScheme 20 will be desirable or necessary for certain embodiments of theinvention. For example, it may be undesirable to subject a compound inwhich X is halo to the catalytic hydrogenolysis steps of Scheme 19because the undesired displacement of the halogen may compete with thedesired hydrogenolysis of the carbon-nitrogen bonds. One alternativestrategy is to postpone the halogenation until after the hydrogenolysis.Another alternative strategy is to use a milder means of reduction thatwould leave the halogen in place. A third alternative, useful in theinstance when the halogen is to serve as a leaving group, is to performthe desired displacement of halogen before the hydrogenolysis step.

Compounds of Formula 1 can be prepared from the compound of structure24, whether it exists as a mixture of stereoisomers or as asubstantially pure enantiomer, using common reagents and methods wellknown in the art. A preferred intermediate to the compounds of theinstant invention is the 6-bromo-derivative. Preferably Z is an aminoblocking group such as benzoyl. A preferred method of introducing thebromo substituent at the 6-position is by reaction with bromine inglacial acetic acid, buffered with sodium acetate. Amino blocking groupscan be added, if desired, to the 4-amino substituent using such methodsas those disclosed by Greene, supra, and Barton, supra. Alkyl groups canbe added, if desired, to the 4-amino substituent using such commonmethods as ammonolysis of the appropriate halide as discussed byMorrison and Boyd, Chapter 22, Organic Chemistry, Third Edition, Allynand Bacon, Boston, 1973, to provide a compound of structure 26 whereinR¹ and R² are defined hereinabove. If desired, the benzoyl group can beremoved from the 1-position using known methods and optionally replacedwith other amino- protecting groups. Preferably the benzoyl grouprepresented by Z is replaced with a triphenylmethyl group in structure28 prior to the metallating step to form structure 2. Theamino-protecting groups and alkyl groups can be added either before orafter the bromination, as desired.

The 4-amino-6-bromotetrahydrobenz[cd]indole starting materials used toprepare the compounds of the invention can be readily prepared by otherprocesses such as depicted in Reaction Scheme 2 disclosed in U.S. Pat.No. 4,576,959 of Flaugh, incorporated herein by reference in itsentirety.

The compound of structure 26can be oxidized to thetetrahydrobenz[cd]indole 28 using oxidizing agents such as manganesedioxide. The compound 28 where X is halo can be metallated as discussedhereinabove to provide the compound of structure 2.

The procedure of Scheme 20 using the 4,5-epoxide provides a convenientway to prepare the optically active isomers of the compounds of thepresent invention. Such isomers can also be isolated by resolvingracemic mixtures. This resolution can be carried out in the presence ofa resolving agent, by chromatography or by repeated crystallization.Particularly useful resolving agents are d- and 1-tartaric acids, d- and1-ditoluoyltartaric acids, and the like.

The methods of preparation described in Schemes 2-19 provide compoundsin which the heteroaromatic ring may or may not be substituted. Thegeneral reactions provided below set forth methodology forincorporating, interconverting, and removing substituents on theheteroaromatic ring. Additional methods for performing thesetransformations are cited in Comprehensive Organic Transformations byRichard C. Larock, VCH Publishers, Inc., New York (1989) which isincorporated herein by reference. "HET" refers to the heteroaromaticattached to the tetrahydrobenz[cd]indole at position C-6.

    ______________________________________                                        1.  Halogen substituent (X):                                                      HET--OH → HET--X                                                                        POX.sub.3, PX.sub.3, SOX.sub.2, PPh.sub.3.X.sub.2,                            or                                                                            P(OR).sub.3.X.sub.2                                          HET--NH.sub.2 → HET--X                                                                  1. HONO; 2. CuX, or KI, or                                                    HBF.sub.4, Δ                                       2.  O(C.sub.1 -C.sub.3 alkyl), i.e., [OR]                                         HET--X → HET--OR                                                                        RO--, CuI, (DMF, or DMAc,                                                     or NMP), Δ                                             HET--OH → HET--OR                                                                       Base, RX; or CH.sub.2 N.sub.2                            3.  Hydroxy substituent:                                                          HET--NH.sub.2 → HET--OH                                                                 1. HONO; 2. H.sub.3 O+, Δ                              HET--OMe → HET--OH                                                                      48% HBr, Δ; or BBr.sub.3                           4.  Cyano Substituent:                                                            HET--NH.sub.2 → HET--CN                                                                 1. HONO; 2. CuCN                                             HET--X → HET--CN                                                                        CuCN, (DMF, or DMAc, or                                                       NMP), Δ;                                                                or CN.sup.-, Δ                                     5.  S(C.sub.1 -C.sub.3 alkyl); i.e., [SR]                                         HET--NH.sub.2 → HET--SR                                                                 1. HONO; 2. RSH, base                                        HET--X → HET--SR                                                                        RS.sup.-, CuI, (DMF, or DMAc, or                                              NMP), Δ                                            6.  Amino substituent:                                                            HET--NO.sub.2 → HET--NH.sub.2                                                           H.sub.2, catalyst (i.e., Pt or                                                Pd)                                                      7.  Hydrogen substituent:                                                         HET--X → HET--H                                                                         H.sub.2, catalyst; or R.sub.3 SnH, 2,2'-                                      azobis(2-methyl)propionitrile),                          Δ                                                                           HET--OH → HET--H                                                                        1. 5-chloro-1-phenyltetrazole                                                 2. H.sub.2, catalyst                                         HET--NH.sub.2 → HET--H                                                                  1. HONO, 2. H.sub.3 PO.sub.2                                 HET--CH.sub.2 Ph → HET--H                                                               H.sub.2, catalyst (i.e., Pd)                                                  (This applies if the                                                          benzyl group is attached                                                      to a nitrogen in the                                                          heterocyclic ring.)                                          HET--SR → HET--H                                                                        Raney Ni                                                 ______________________________________                                    

6-acyl-substituted-tetrahydrobenz[cd]indoles are preferred intermediatesin the preparation of certain of the compounds of the instant invention,particularly 6-isoxazole-indoles and 6-pyrazole-indoles. The 6-acylsubstituted indoles can be prepared by several routes using the6-iodo-substituted indole of structure 30 as depicted in Scheme 21 whereR¹, R² and Z are as defined hereinabove. ##STR13##

In a preferred method of preparation as depicted in Scheme 21, thenitrile 32is contacted with an organometallic reagent such as a Grignardreagent under standard conditions to provide the 6-acyl derivative 34.For this reaction Z is preferably triisopropysilyl. Alternatively, a6-alkyne intermediate of structure 36can be prepared and then hydrolyzedto provide the acyl derivative 38. This method provides a methylenegroup adjacent to the carbonyl group. In this method Z can be an aminoprotecting group such as benzoyl although the unprotected 1-nitrogen ispreferred, i.e., Z is hydrogen. Compounds of structure 30 can becontacted with a palladium catalyst Pd(PPh₃)₄ [where Ph is phenyl] andthe tin alkyne compound R¹² --C═--Sn(CH₃)₃ wherein R¹² is a C₁ -C₇alkyl, substituted C₁ -C₇ alkyl, aryl (C₁ -C₃ alkyl), substituted aryl(C₁ -C₃ alkyl), or C₃ -C₇ cycloalkyl. This reaction is normallyconducted in a solvent such as toluene at an elevated temperature, forexample at about 100° C. Typically an excess of the tin alkyne is usedalong with about 0.25 equivalents of the palladium compound based oncompound 30. The 6-alkyne 36 is then contacted with HgSO₄ in water toprovide the ketone 38. If desired the corresponding1,2,2a,3,4,5-hexahydrobenz[cd]indole can be used in a reaction schemesimilar to that of Scheme 21 followed by an oxidation step to providestructure 38. In this case the preferred blocking group for the1-nitrogen, i.e., Z, is benzoyl or trityl.

In another preparation method depicted in Scheme 22, the 6-iododerivative 30 can be used to prepare certain 6-acyl compounds directly.This is accomplished by contacting the 6-iodo compound with atrialkyltinalkyl complex and carbon monoxide in the presence of apalladium catalyst Pd(PPh₃)₄ [where Ph is phenyl] as described in theliterature for arylhalides. [A. Schoenberg and R. F. Heck, J. Org.Chem., 39, p. 3327 (1974); and A. Schoenberg, I. Bartoletti, and R. F.Heck, J. Org. Chem. 39, p. 3318 (1974)]. Although a blocking group Zsuch as diethylcarbamoyl can be used for this method, the method canalso be accomplished When Z is hydrogen, or the blocking group can beremoved to provide compounds of structure 40 where R¹, R² and R¹² are asdefined above. Alternatively the corresponding indoline can be used inthe sequence of Scheme 22 followed by an oxidation step to providestructure 4.0. ##STR14##

As those skilled in the art will recognize, variations of any of thereaction schemes, reagents and procedures discussed herein may bedesirable or necessary for certain embodiments of the invention. Suchvariations are contemplated as within the scope of the presentinvention.

The following examples further illustrate the preparation of thecompounds of this invention. The examples are provided for purposes ofillustration only and are not to be construed as limiting the scope ofthe instant invention in any way.

The terms and abbreviations used in the instant examples have theirnormal meaning unless otherwise designated, for example, "° C." refersto degrees celsius; "N" refers to normal or normality; "mmol" refers tomillimole; "g" refers to gram; "mL" means milliliter; "M" refers tomolar; "min" refers to minutes; "hr" refers to hours; "NMR" refers tonuclear magnetic resonance; and "MS" refers to mass spectrometry.

EXAMPLE 1

A. Preparation of(±)-1-Benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

To a solution of(±)-1-benzoyl-6-bromo-4-(di-n-propylamino)hexahydrobenz[cd]indole (5.5g, 12.5 mmol) in DMF (100 mL) under a N₂ atmosphere was added 3.4 g(37.5 mmol) of CuCN and 7.1 g (37.5 mmol) of CuI. The reaction mixturewas then stirred at 140° C. for 6 hr. The reaction mixture was pouredonto ice, diluted with water, CH₂ Cl₂ added and stirred for 30 minutes.The mixture was filtered through a Celite pad and the filtrate wasextracted twice with CH₂ Cl₂. The organic solution was washed twice withsaturated NaCl solution. The CH₂ Cl₂ solution was dried over MgSO₄ andthen evaporated to provide 4 g of a solid. Chromatography of this crudeproduct over silica gel with 1:19 MeOH/CH₂ Cl₂ as eluent gave 3 g (62%)of product. mp=122°-124° C.

B. Preparation of(-)(2aS,4R)-1-Benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole,

To a solution of (-)(2aS,4R)-6-bromo compound (30.0 g; 0.068 mol) in 500ml of DMF was added CuCN (18.3 g; 0.2 mol) and CuI (38.0 g; 0.2 mol).The reaction mixture was then stirred at 140° C. for 6 hr. The reactionmixture was poured into 4L of water. The precipitate was collected andwashed several times with water. The precipitate was suspended in diluteNH₄ OH and slurried with ethyl acetate. .The whole mixture was filteredthrough a celite pad. The ethyl acetate solution was separated andwashed with brine solution. The ethyl acetate solution was dried (MgSO₄)and concentrated to dryness to provide 21.3 g of the (-)-6-nitrile.

C. Preparation of the (+)(2aR,4S)-6-cyano counterpart of Example 1B.

In a similar manner as in Example 1B above, the (+)(2aR,4S)-6-bromocompound (17.1 g, 0.039 mol) was contacted with CuCN (10.75 g; 0.12 mol)and CuI (22.8 g; 0.12 mol) in 300 ml DMF to give 11.6 g of (+)-6-cyanocompound.

EXAMPLE 2

Preparation of(±)-6-Cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.

To a stirred solution of 4.8 g (0.0124 mol) of(±)-1-benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indolein 200 mL of THF cooled to -78° C. under a N₂ atmosphere were added 16mL (0.025 mol) of a 1.6M solution of n-butyl lithium in hexane. Thereaction mixture was stirred at -78° C. for 30 minutes and then allowedto warm to -20° C. To the reaction mixture was added 100 mL of 1N HCl.The mixture was extracted once with ethyl ether. The acidic solution wasmade alkaline with the addition of cold 5N NaOH. The basic mixture wasextracted twice with CH₂ Cl₂. The combined organic solution was washedwith a saturated NaCl solution. The CH₂ Cl₂ solution was dried overMgSO₄ and evaporated to give 4 g of an oil. Chromatography of this oilover silica gel with ethyl acetate as eluent gave 3 g (85%) of productas an oil which upon standing solidified.

EXAMPLE 3

Preparation of(+)(2aS,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.

To a solution of(+)(2aS,4R)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(12.8 g, 0.045 mol) and triethylamine (4.5 g, 0.045 mol) in 400 mL ofmethylene chloride was added a solution of triphenylmethyl chloride(trityl chloride) (12.6 g, 0.045 mol) in 100 mL of methylene chloridedropwise at room temperature. The reaction mixture was stirred for 16 hrat room temperature. The reaction mixture was extracted with water andcold 1N HCl. The organic solution was washed with a saturated NaHCO₃solution and with a saturated brine solution. The organic layer wasdried (MgSO₄) and concentrated to dryness in vacuo to give a residue.The residue was slurried with warm hexanes, cooled and filtered toremove insolubles. The filtrate was concentrated to an oil. The oil waschromatographed (silica gel, 20% ethyl acetate in hexanes) to provide20.6 g of the (+)-trityl nitrile.

EXAMPLE 4

Preparation of(+)(2aS,4R)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.

A solution of 2.4 g (4.6 mmol) of(+)(2aS,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indolein 100 mL of THF was treated with 25 mL of 2.0M methylmagnesium bromidein diethyl ether. The reaction mixture was refluxed for 16 hr. Thereaction mixture was cooled and excess Grignard reagent was decomposedwith addition of a saturated NH₄ Cl solution. The reaction mixture wasextracted with ethyl acetate. The organic solution was evaporated to anoil. The oil was dissolved in 25 mL of 5N HCl and the solution wasstirred at room temperature for 30 min. The acidic solution was madealkaline with the addition of excess concentrated NH₄ OH solution. Thebasic mixture was extracted twice with ethyl acetate. The combinedorganic solution was washed once with a saturated NaCl solution anddried over MgSO₄. The ethyl acetate solution was evaporated to yield 1.4g of an oil. Chromatography of this oil over silica gel with ethylacetate as eluent gave 1.2 g (87%) of product. Recrystallization fromhexanes yielded 840 mg of the product (+) ketone.

mp=121°-122° C. [α]_(D) +67.40° (MeOH).

EXAMPLE 5

Preparation of(±)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.

A solution of 0.5 g (1.8 mmol) of(±)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indolein 75 mL of benzene was treated with 5 mL of 2.0M methylmagnesiumbromide in diethyl ether. The reaction mixture was refluxed for 2 days.The reaction mixture was cooled and excess Grignard reagent wasdecomposed with addition of a saturated NH₄ Cl solution. The benzenelayer was separated and washed once with a saturated NaCl solution. Theorganic solution was evaporated to an oil. The oil was dissolved in 25mL of 5N HCl and the solution was stirred at room temperature for 30min. The acidic solution was made alkaline with the addition of excessconcentrated NH₄ OH solution. The basic mixture was extracted twice withCH₂ Cl₂. The combined organic solution was washed once with a saturatedNaCl solution and dried over MgSO₄. The CH₂ Cl₂ solution was evaporatedto yield 0.5 g of an oil. Chromatography of this oil over silica gelwith ethyl acetate as eluent gave 0.4 g (75%) of product as an oil whichupon standing solidified.

mp=76°-77° C.

EXAMPLE 6

Preparation of(+)(2aS,4R)-6-(3-pyrazoyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.2HCl.

A solution of(+)(2aS,4R)-1-triphenylmethyl-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-tris(dimethylamino)methanein 50 mL of toluene was refluxed for 5 hr. The reaction was concentratedin vacuo and the residue was dissolved in 100 mL of CH₃ OH. To the CH₃OH solution was added 2 mL of 85% hydrazine and the reaction mixture wasstirred at room temperature for 16 hours. To the reaction mixture wasadded 50 ml of 1N HCl and stirred for an additional 1 hr. The solutionwas concentrated in vacuo to remove CH₃ OH and the acidic solution wasextracted with ethyl acetate. The acidic solution was separated and madealkaline with addition of excess concentrated NH₄ OH. The basic mixturewas extracted with ethyl acetate. The ethyl acetate solution was washedwith a brine solution, dried (MgSO₄) and concentrated in vacuo provide900 mg of an oil. The crude product was chromatographed through silicagel (flash column, ethyl acetate) to yield 700 mg of pyrazole compound.The oil was dissolved in 50 mL of CH₃ OH and 2 equivalents of 0.1N HCLwas added to the solution. The solution was concentrated in vacuo andthe residue was crystallized from ethanol/diethyl ether.

Yield--400 mg mp=260 d MS m/e 324(FD) [α]_(D) =+19.84° (MeOH). Analysiscalculated for C₂₀ H₂₈ N₄.2HCl Theory: C, 60.45; H, 7.61; N, 14.10;Found: C, 60.21; H, 7.60; N, 14.26.

EXAMPLE 7

Preparation of(±)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahvdrobenz[cd]indole.2HCl.

To a solution of(±)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(2.3 g, 7.7 mmol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH₂ Cl₂under N₂ was added dropwise a solution of 2,2,2-trichloroethylchloroformate. The reaction mixture was stirred at room temperature for1 hr. The CH₂ Cl₂ solution was extracted with water and 1N HCl. Theorganic solution was washed with a saturated NaHCO₃ solution and with abrine solution. The CH₂ Cl₂ solution was dried (MgSO₄) and concentratedin vacuo to give 3.3 g of the 1-carbamylindoline.

A solution of this 1-carbamylindoline (3.3 g, 7.7 mmol) andtris(dimethylamino)methane (5 mL) in 70 mL of toluene was stirred atreflux for 16 hr. The reaction mixture was concentrated to dryness invacuo. The residue was dissolved in 50 mL of acetic acid andhydroxylamine hydrochloride (2.5 g, 36 mmol) was added. The reactionmixture was stirred at room temperature for 16 hr and then concentratedin vacuo to dryness. The residue was suspended in water and excessconcentrated NH₄ OH was added to the mixture. The basic mixture wasextracted with CH₂ Cl₂. The organic solution was washed with a brinesolution, dried (MgSO₄) and concentrated in vacuo to give 3.1 g of anoil. The crude product was chromatographed (flash column, silica gel,20% hexanes in ethyl acetate) to yield 2.0 g of(±)-1-carbamyl-6-isoxazolylindoline.

This isoxazole carbamate was dissolved in 20 mL of acetic acid and 1 gof zinc dust was added all at once. The reaction mixture was stirred atroom temperature for 4 hr. The reaction mixture was filtered through acelite pad and the filtrate was concentrated to dryness in vacuo. Theresidue was suspended in a saturated NaHCO₃ solution and extracted withCH₂ Cl₂. The organic solution was washed with a brine solution, dried(MgSO₄) and concentrated to an oil. The crude material waschromatographed (flash column, silica gel, ethyl acetate) to give 500 mgof isoxazole indoline. The product was dissolved in 50 mL of CH₃ OH and2 equivalents of 0.1N HCl were added. The solution was concentrated todryness and the residue was crystallized from ethanol/diethyl ether togive 85 mg of 5-isoxazole-6-substituted product as the dihydrochloride.

mp=226° C d MS m/e 325(FD) Analysis calculated for C₂₀ H₂₇ N₃ O.2HClTheory: C, 60.30; H, 7.34; N, 10.55; Found: C, 58.83; H, 7.18; N, 10.01.

EXAMPLE 8

Preparation of(+)(2aS,4R)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahvdrobenz[cd]indole.2

A solution of(+)(2aS,4R)-1-triphenylmethyl-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole(3.33 g, 6 mmol), 5 g hydroxylamine hydrochloride, 20 ml pyridine and 30mL of ethanol was refluxed for 16 hr. The reaction mixture wasconcentrated to dryness in vacuo and the residue was dissolved in 5NHCl. The acidic mixture was extracted with ethyl acetate. The acidicsolution was made alkaline with excess NH₄ OH solution and extractedwith ethyl acetate. The ethyl acetate solution was washed with a brinesolution, dried (MgSO₄) and concentrated in vacuo to give 1.5 g of crudeproduct which was chromatographed (flash column, silica gel, ethylacetate) to give 1.2 g of oxime.

mp=129°-130° C.

To a solution of this oxime (1.2 g, 3.8 mmol) in 100 mL of THF cooled to-5° C. under a N₂ atmosphere was added 7.5 mL n-butyllithium (1.6M inhexanes) dropwise with stirring. The reaction mixture was stirred withcontinued cooling for 1 hr. To the reaction mixture was added 2 mL (26mmol) of DMF all at once and then stirred for 1 hr at room temperature.The reaction mixture was poured into 50 mL of 1N H₂ SO₄ and the acidicsolution was warmed on a steam bath for 1 hr. The acidic solution wascooled, extracted with diethyl ether, and then made alkaline with excess5N NaOH. The basic mixture was extracted with ethyl acetate. The organicwas layer was washed with a brine solution, dried (MgSO₄) andconcentrated in vacuo to give 1 g of an oil. The oil was chromatographed(flash column, silica gel, ethyl acetate) to yield 500 mg of product asan oil. The oil was dissolved in 50 mL of CH₃ OH and 2 equivalents of0.1N HCL were added. The solution was concentrated to dryness in vacuoand the residue was crystallized from ethanol/diethyl ether.Crystallization gave 300 mg of the dihydrochloride of the6-(3-isoxazolyl) product.

mp=215° C. d MS m/e 325 (FD) [α]_(D) 26.4° (MeOH).

EXAMPLE 9

Preparation of(±)-1-benzoyl-6-[4-(2-aminothiazolyl)]-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.

To a solution of(±)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(205 mg, 0.7 mmol) and triethylamine (81 mg, 0.8 mmol) in 20 mL of CH₂Cl₂ was added a solution of benzoyl chloride (112 mg, 0.8 mmol) in 20 mLof CH₂ Cl₂. The reaction mixture was stirred at room temperature for 2hr. The reaction mixture was sucessively washed with water, a saturatedNaHCO₃ solution, a brine solution and dried (MgSO₄). The organic layerwas concentrated to dryness in vacuo to give 200 mg of the 1-benzoylderivative.

A solution of this N-benzoyl compound (200 mg, 0.5 mmol) in 20 mL ofacetic acid was saturated with HBr(gas). To the solution was addeddropwise a solution of bromine (0.2 mL) in 5 mL of acetic acid. Thereaction was stirred at room temperature for 30 min and thenconcentrated to dryness in vacuo. The residue was dissolved in 30 mL ofethanol then 500 mg of thiourea were added and the mixture refluxed for16 hr. The reaction was concentrated to dryness in vacuo and the residuedissolved in water. The solution was made alkaline with the addition ofconcentrated NH₄ OH. The basic mixture was extracted with CH₂ Cl₂. Theorganic solution was washed with a brine solution, dried (MgSO₄) andevaporated to dryness to give 200 mg of an oil. The oil waschromatographed (flash column, silica gel, ethyl acetate) to provide 140mg of the named 6-aminothiazolyl compound. MS m/e 460(FD)

EXAMPLE 10

Preparation of(+)(2aS,4R)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.2HCl

To a solution of(+)(2aS,4R)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(1.7 g, 5.7 mmol) and triethylamine (0.8 ml, 6 mmol) in 90 ml CH₂ Cl₂was added dropwise a solution of 2,2,2-trichloroethylchloroformate (1.3g, 6 mmol) in 10 ml CH₂ Cl₂. The reaction mixture was stirred at roomtemperature for one hour and then extracted with water and 1N HCl. Theorganic solution was washed with a saturated NaHCO₃ solution, asaturated brine solution, dried over MgSO₄ and then concentrated todryness in vacuo to give 2.5 g of the 1-carbamylindoline.

A solution of the 1-carbamylindoline (2.5 g, 5.7 mmol) andtris(dimethylamino)methane (5 ml) in 100 ml of toluene was stirred atreflux for 16 hours. After 16 hours the reaction mixture wasconcentrated to dryness in vacuo. The resulting residue was dissolved in50 ml of acetic acid and 1.5 g (22 mmol) of a hydroxylaminehydrochloride solution were added. The resulting reaction mixture wasstirred at room temperature for 16 hours and then concentrated todryness in vacuo. The resulting residue was suspended in water and anexcess of a concentrated NH₄ OH solution was added to the mixture. Thebasic mixture was then extracted with CH₂ Cl₂ and the resulting organicextract was washed with a saturated brine solution, dried over MgSO₄ andthen concentrated in vacuo to give 2.1 g of an oil. This oil waschromatographed (flash column, silica gel, EtOAc) to yield 1.9 g of(+)(2aS,4R)-6-(5-isoxazolyl)indoline. The isoxazolylindoline wasdissolved in 30 ml of acetic acid and 1.5 g of zinc dust were added allat once. The resulting reaction mixture was stirred at room temperaturefor four hours and then filtered through a celite pad. The filtrate thusobtained was then concentrated to dryness in vacuo. The resultingresidue was suspended in a saturated NaHCO₃ solution, which was thenextracted with CH₂ Cl₂. The organic extract was then washed with asaturated brine solution, dried over MgSO₄ and concentrated in vacuo toan oil. This oil was chromatographed (flash column, silica gel, EtOAc)to give 400 mg of isoxazolylindoline. Such compound was dissolved in 50ml of methanol and two equivalents of 0.1N HCl were added. The resultingsolution was concentrated to dryness in vacuo and the resulting residuewas then crystallized from ethanol/diethyl ether to give 170 mg of titlecompound.

mp=235° C. d MS m/e 325(FD) [α]_(D) +27.29° (MeOH) Analysis calculatedfor C₂₀ H₂₇ N₃ O.2HCl Theory: C, 60.30; H, 7.34; N, 10.55; Found: C,60.53; H, 7.54; N, 10.26.

EXAMPLE 11

Preparation of (-)(2aR,4S)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahvdrobenz[cd]indole.2HCl

The title compound was prepared substantially in accordance with themethod described in Example 10, above, utilizing 2.5 g (8.3 mmol) of(-)(2aR,4S)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (prepared substantially in accordance withthe method described in Example 4) and 1.5 g (22 mmol) of ahydroxylamine hydrochloride solution. Such reaction sequence provided500 mg of title compound.

m.p. 235° C. d MS m/e 325(FD) [α]_(D) -29.18° (MeOH) Analysis calculatedfor C₂₀ H₂₇ N₃ O.2HCl Theory: C, 60.30; H, 7.34; N, 10.55; Found: C,60.11; H, 7.41; N, 10.43.

EXAMPLE 12

Preparation of(2aR,4S)-6-(3-phenyl-1,2,4-oxadiazol-5-yl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole

A sodium ethoxide solution was prepared by dissolving 49 mg (2.1 mmol)of sodium in 35 ml of ethanol. Phenylhydroxamidine (1.73 g, 12.71 mmol)and6-ethoxycarbonyt-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(890 mg, 2.1 mmol) were added to the ethoxide solution and the resultingsolution was heated to reflux and stirred at that temperature for 6.25hours and then stirred overnight at room temperature. The next morningadditional sodium ethoxide solution (50 mg of sodium in 10 ml ofethanol) was added and the reaction mixture was again stirred at refluxovernight. The next morning water was added to the reaction mixture andthe resulting solution was then extracted with ethyl acetate. Theorganic extract was washed sequentially with water and a saturated brinesolution, dried over sodium sulfate and then concentrated in vacuo toprovide 2.33 g of a brown oil. This oil was purified by flashchromatography (2.5% isopropanol in chloroform plus 0.5% ammoniumhydroxide) to provide 260 mg of title product as a light yellow solid.Such product was purified by recrystallization from hexane.

Analysis calculated for C₂₅ H₃₀ N₄ O: Theory: C, 74.59; H, 7.51; N,13.92; Found: C, 74.59; H, 7.52; N, 13.90.

EXAMPLE 13

Preparation of(-)(2aR,4S)-6-(2-furyl)-4-(di-n-propylamino)-1,2,2a3,4,5-hexahydrobenz[cd]indole

To a sealable tube with threads containing 13 ml of dry tetrahydrofuranwere added 1.2 g (2.46 mmol) of(+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole,968 mg (2.71 mmol) of 2-(tributylstannyl)furan and 200 mg ofbis(triphenyl-phosphine)palladium(II) chloride. The resulting mixturewas then deaerated with argon for 15 minutes. After deaeration, the tubewas sealed with a teflon cap and the contents thereof were heated to100° C. for 24 hours. After 24 hours, the reaction mixture was cooled,filtered through a celite pad and the resulting filtrate was thenconcentrated in vacuo to provide a viscous orange oil. Flashchromatography of this oil over silica gel with 60% ethyl acetate/hexaneplus 0.5% ammonium hydroxide as eluent gave the protected analog of thetitle compound in 61% yield.

The above-mentioned protected analog (635 mg, 1.4 mmol) was dissolved in10 ml of dry tetrahydrofuran and the resulting solution was chilled to-78° C. Once chilled, 1.5 ml (2.39 mmol) of a 1.7M solution ofn-butyllithium in hexane was added dropwise via syringe. Oncen-butyllithium addition was complete the reaction mixture was warmed toroom temperature. The reaction mixture was quenched with a saturatedNaHCO₃ solution and then partitioned between ethyl acetate and water.The aqueous layer was extracted with ethyl acetate, and the organiclayers were combined, washed with a saturated brine solution, dried oversodium sulfate and then concentrated in vacuo to provide a viscousorange oil. This oil was chromatographed over silica gel (elution with20% ethyl acetate/hexane plus 0.5% ammonium hydroxide) to provide 161 mgof title compound as a pale yellow oil.

MS m/e 324(FD) [α]_(D) -45.63° (^(MeOH)) Analysis calculated for C₂₁ H₂₈N₂ O: Theory: C, 77.74; H, 8.70; N, 8.63; Found: C, 78.74; H, 8.82; N,8.27.

EXAMPLE 24

Preparation of(+)(2aS,4R)-6-(2-furyl)-4-(di-n-propylamino)-1,2,2a3,4,5-hexahydrobenz[cd]indole

The title compound was prepared substantially in accordance with themethod set forth in Example 13, above, utilizing 1.5 g (3.07 mmol) of(-)(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole,250 mg of bis(triphenylphosphine)palladium(II) chloride and 1.21 g (3.38mmol) of 2-(tributylstannyl)furan to provide 592 mg of title compound asa viscous brown oil.

MS m/e 325.22(FD) [α]_(D) +42.0° (MeOH) Analysis calculated for C₂₁ H₂₈N₂ O: Theory: C, 77.74; H, 8.70; N, 8.63; Found: C, 77.59; H, 8.10; N,8.83.

EXAMPLE 15

Preparation of(+)(2aS,4R)-6-(3-furyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahvdrobenz[cd]indole

The title compound was prepared substantially in accordance with themethod described in Example 13, above, utilizing 1.50 g (3.07 mmol) of(+)(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole,1.21 g (3.38 mmol) of 3-(tributylstannyl)furan and 250 mg ofbis(triphenylphosphine)palladium(II) chloride to provide 711 mg of titleproduct as a pale yellow viscous oil.

MS m/e 324(FD) Analysis calculated for C₂₁ H₂₈ N₂ O: Theory: C, 77.24;H, 8.70; N, 8.63; Found: C, 77.49; H, 8.68; N, 8.45.

EXAMPLE 16

Preparation of(+)(2aS,4R)-6-(2-thienyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

The title compound was prepared substantially in accordance with themethod set forth in Example 13, above, utilizing 1.5 g (3.1 mmol) of(-)(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole,150 mg of bis(triphenyl-phosphine)palladium(II) chloride and 1.27 g(3.41 mmol) of 2-(tributylstannyl)thiophene to provide 719 mg of titlecompound as a light brown viscous oil.

MS m/e 341(FD) Analysis calculated for C₂₁ H₂₈ N₂ S: Theory: C, 74.07;H, 8.29; N, 18.60; S, 9.42; Found: C, 74.24; H, 8.60; N, 17.52; S, 9.15.

EXAMPLE 17

Preparation of(+)(2aS,4R)-6-(2-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

The title compound was prepared substantially in accordance with themethod set forth in Example 13, above, utilizing 1.50 g (3.07 mmol) of(-)(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz-[cd]indole,250 mg of bis(triphenylphosphine)palladium(II) chloride and 1.24 g (3.38mmol) of 2-(tributylstannyl)-pyridine to produce 474 mg of titlecompound as a colorless foam. The hydrochloride salt of the titlecompound was prepared by dissolving the foam in diethyl ether and thentreating the resulting solution with a saturated hydrochloric acid inmethanol solution. A yellow foam comprised of such salt was affordedafter concentration in vacuo.

MS m/e 336.24(FD) Analysis calculated for C₂₂ H₂₉ N₃.HCl: Theory: C,71.04; H, 8.13; N, 11.30; Found: C, 70.60; H, 8.46; N, 10.58.

EXAMPLE 18

Preparation of(+)(2aS,4R)-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahvdrobenz[cd]indole

The title compound was prepared substantially in accordance with theprocedure set forth in Example 13, above, utilizing 1.50 g (3.07 mmol)of(-)(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole,250 mg of bis(triphenylphosphine)-palladium(II) chloride and 1.24 g(3.38 mmol) of 3-(tributylstannyl)pyridine to produce 475 mg of titlecompound as a pale yellow oil. The dihydrochloride salt of the titlecompound was prepared by dissolving the oil in diethyl ether and thenadding a saturated hydrochloric acid in methanol solution dropwise. Oncean excess of hydrochloric acid had been added the mixture wasconcentrated in vacuo to provide a pale yellow foam.

MS m/e 336.24(FD) Analysis calculated for C₂₂ H₂₉ N₃.2HCl: Theory: C,64.70; H, 7.65; N, 10.29; Found: C, 65.84; H, 7.55; N, 9.76.

EXAMPLE 19

Preparation of(-)(2aR,4S)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a3,4,5-hexahydrobenz[cd]indole

A. 2-tributylstannyloxazole

A solution of 1.00 g (14.5 mmol) of oxazole in 25 ml of THF at -78° C.was treated with 10.2 ml (14.6 mmol) of 1.43M butyllithium in hexane.After stirring for 30 minutes, an addition of 3.93 ml (14.5 mmol) oftributyltin chloride was made, and the solution was allowed to warm toroom temperature. Stirring was continued for another hour after whichmost of the solvents were evaporated in vacuo. The resulting residue wastaken up in 50 ml of hexane, and the resulting precipitate was separatedby filtration through filtercel. Evaporation of the solvent from thefiltrate provided 5.13 g of a colorless oil which was identified by NMRas the 2-stannyl derivative plus a small amount of tetrabutylstannane.

B.(-)(2aR,4S)-l-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazoleprepared above and 6.8 g (13.9 mmol) of(+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indolein 100 ml of toluene was treated with 0.7 g (0.6 mmol) oftetrakis-(triphenylphosphine)palladium then refluxed under nitrogen for20 hours. After cooling the reaction mixture was washed with a saturatedbrine solution and then dried over Na₂ SO₄. Concentration in vacuoprovided a viscous oil which was chromatographed over a silica gelcolumn using a solvent gradient progressing from toluene to 1:1toluene/EtOAc. The product from the column was dissolved in 1M HCl. Thissolution was then washed with ether, made alkaline with 5M NaOH, andextracted with CH₂ Cl₂. Concentration of the extract in vacuo gave about4 g of a brown oil. When this oil was dissolved in pentane a smallamount of a red/brown resin separated leaving a clear, yellow solution.The resin was separated and the pentane was evaporated to provide aresidue. This residue was crystallized by dissolving it in a smallamount of CH₂ Cl₂ and slowly adding isoctane. The crystalline(-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole,obtained in four crops, weighed 2.63 g. m.p. 103°-104° C.

C.(-)(2aR,4S)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A solution of 1.00 g (2.33 mmol) of the above 1-benzoyl compound in 25ml of THF was stirred at -78° C. as 3.0 ml (4.29 mmol) of 1.43Mbutyllithium in hexane was added. The resulting solution was allowed towarm to 0° C., then poured into water and extracted with CH₂ Cl₂. TheCH₂ Cl₂ extract was then, in turn, extracted with 1M HCl. The resultingaqueous extract was made alkaline with 1M NaOH, and, in turn, extractedwith CH₂ Cl₂. After drying over Na₂ SO₄, the extract was concentrated invacuo to provide title compound as a viscous oil. m.p. 103°-104° C.

MS m/e 326 [α]_(D) =-60° (C=i, MeOH) . Analysis calculated for C₂₀ H₂₇N₃ O: Theory: C, 73.81; H, 8.36; N, 12.91; Found: C, 73.37; H, 8.26; N,12.09.

EXAMPLE 20

Preparation of(-)(2aR,4S)-6-(5-isoxazolyl)-4-[di-(cyclopropylmethyl)amino]-1,2,2a,3,4,5-hexahydro-benz[cd]indole

To a solution of(-)(2aR,4S)-6-acetyl-4-[di-(cyclopropylmethyl)amino]-1,2,2a,3,4,5-hexahydrobenz-[cd]indole(2.5 g, 7.7 mmol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH₂ Cl₂was added dropwise a solution of 2,2,2-trichloroethylchloroformate (1.7g, 8 mmol) in 10 ml CH₂ Cl₂. The reaction mixture was stirred at roomtemperature for one hour and then extracted with water and 1N HCl. Theorganic solution was washed with a saturated NaHCO₃ solution, and asaturated brine solution, dried over MgSO₄ and then concentrated todryness in vacuo to give 3.1 g of the 1-carbamylindoline.

A solution of the 1-carbamylindoline (3.1 g, 6.2 mmol) andtris(dimethylamino)methane (5 ml) in 100 ml of toluene was stirred atreflux for 16 hours. After 16 hours the reaction mixture wasconcentrated to dryness in vacuo. The resulting residue was dissolved in50 ml of acetic acid and 2.0 g (29 mmol) of hydroxylamine hydrochloridewere added. The resulting reaction mixture was stirred at roomtemperature for 16 hours and then concentrated to dryness in vacuo. Theresulting residue was suspended in water and an excess of a concentratedNH₄ OH solution was added to basify the mixture. The basic mixture wasthen extracted with CH₂ Cl₂ and the resulting organic extract was washedwith a saturated brine solution, dried over MgSO₄ and then concentratedin vacuo to give 2.1 g of an oil. This oil was chromatographed (flashcolumn, silica gel, EtOAc) to yield 1.7 g of the protected(+)(2aR,4S)-6-(5-isoxazolyl)indoline.

The protected isoxazolylindoline (1.7 g, 3.2 mmol) was dissolved in 30ml of acetic acid and 1.5 g of zinc dust were added all at once. Theresulting reaction mixture was stirred at room temperature for fourhours and then filtered through a celite pad. The filtrate thus obtainedwas then concentrated to dryness in vacuo. The resulting residue wassuspended in a saturated NaHCO₃ solution then extracted with CH₂ Cl₂.The organic extract was then washed with a saturated brine solution,dried over MgSO₄ and concentrated in yacuo to an oil. This oil waschromatographed (flash column, silica gel, EtOAc) to give 660 mg oftitle compound.

EXAMPLE 21

Preparation of(-)(2aR,4S)-6-(5-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A.(-)(2aR,4S)-6-bromo-l-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

To a stirred solution of 12.8 g (29 mmol) of(+)(2aR,4S)-1-benzoyl-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indolein 200 ml of tetrahydrofuran cooled to -78° C. under a nitrogenatmosphere was added 20 ml (32 mmol) of a 1.6M solution ofn-butyllithium in hexane. The reaction mixture was stirred at -78° C.for 30 minutes and then allowed to warm to -20° C. To the reactionmixture was added 50 ml of a 1N hydrochloric acid solution. The mixturewas extracted once with diethyl ether. The acidic solution was madealkaline with the addition of cold 5N sodium hydroxide solution. Thebasic mixture was extracted twice with methylene chloride. The combinedorganic solution was washed with a saturated sodium chloride solution.The methylene chloride solution was dried over magnesium sulfate andevaporated to give 9.6 g of(-)(2aR,4S)-6-bromo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.

To a solution of the above product (9.6 g, 0.028 mol) and triethylamine(3.03 g, 0.03 mol) in 100 ml of methylene chloride was added a solutionof trityl chloride (7.8 g, 0.028 mol) in 100 ml of methylene chloridedropwise at room temperature. The reaction mixture was stirred for 16hours at room temperature. The reaction mixture was extracted with waterand a cold 1N hydrochloric acid solution. The organic solution waswashed with a saturated sodium bicarbonate solution and with a saturatedbrine solution. The organic solution was dried over magnesium sulfateand concentrated to dryness in vacuo to give a residue. The residue wasslurried with warm hexane, cooled and filtered to remove insolubles. Thefiltrate was concentrated to an oil. The oil was chromatographed (silicagel, 20% ethyl acetate in hexane) to provide 12.7 g of the above-titledcompound.

B.(-)(2aR,4S)-6-formyl-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

To a solution of(-)(2aR,4S)-6-bromo-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(6.8 g, 12 mmol) in 100 ml of tetrahydrofuran cooled to -78° C. under anitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithiumin hexane. The reaction mixture was stirred at -78° C. for 1 hour.Dimethylformamide (3 ml) was added to the reaction mixture and themixture was stirred at room temperature for 30 minutes. The reactionmixture was quenched with water and then extracted with ethyl acetate.The ethyl acetate solution was washed with a saturated brine solution,dried over magnesium sulfate and concentrated to dryness to provide 5.6g of the above-titled compound as an oil.

C.(-)(2aR,4S)-6-(5-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A reaction mixture of(-)(2aR,4S)-6-formyl-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(1.06 g, 2 mmol), tosylmethyl isocyanide (390 mg, 2 mmol) and potassiumcarbonate (304 mg, 2.2 mmol) in 100 ml of methanol was stirred at refluxtemperature under a nitrogen atomosphere for 16 hours. The reactionmixture was concentrated to dryness and water was added to the residue.The aqueous mixture was extracted with ethyl acetate. The ethyl acetatesolution was washed with a saturated brine solution, dried overmagnesium sulfate and concentrated to dryness to yield 1 g of an oil.The oil was dissolved in 20 ml of tetrahydrofuran and 50 ml of 5Nhydrochloric acid solution. The reaction mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was extracted twicewith ethyl acetate and the acidic solution was then made alkaline byaddition of excess concentrated ammonium hydroxide solution. The basicmixture was extracted twice with ethyl acetate. The ethyl acetatesolution was washed with a saturated brine solution, dried overmagnesium sulfate and concentrated to dryness to provide 0.5 g of anoil. The oil was purified by silica gel chromatography, with ethylacetate as eluent, to give 0.3 g of title compound.

MS (FD) m/e/325

EXAMPLE 22

Preparation of(2aR,4S)-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A. 3-pyridylboronic acid

A solution of 4.0 ml (6.56 g, 42 mmol) of 3-bromopyridine and 9 ml (8mmol) of trimethylborate in 100 ml of diethyl ether was cooled to -70°C. then treated slowly with 33 ml (83.8 mmol) of a 2.54Mtert-butyllithium in pentane solution. After allowing the resultingslurry to warm to room temperature the solvents were evaporated undervacuum. The residual oil was treated carefully with 50 ml of a 1Mhydrochloric acid solution. Several milliters of methylene chloride wereadded and the mixture was stirred until the oil had dissolved. Theaqueous layer was washed with fresh methylene chloride. The pH of theaqueous solution was raised to 12 with 5M sodium hydroxide solution andthe washing was repeated. The pH of the aqueous solution was thenlowered to 6.5 with concentrated hydrochloric acid solution. Afterchilling, this solution was filtered, saturated with sodium chloride,then extracted several times with a 2:1 mixture of diethyl ether andisopropanol. Evaporation of these extracts produced a colorless solid.This material was further purified by dissolving in methanol,evaporating to a thick paste, adding a few milliliters of water,concentrating further under vacuum, then chilling and collecting thecrystalline product. Additional product in the aqueous mother liquor wasisolated by repeating this process. Thorough drying of this hydratedproduct at 0.1 mm pressure afforded a fine powder weighing 2.2 g.Elemental analysis and a mass spectrum indicated the product so isolatedwas primarily the anhydride (tripyridylboroxane).

B.(2aR,4S)-1-benzoyl-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A solution of 4.00 g of(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indoleand 0.60 g (0,525 mmol) of tetrakis(triphenylphosphine)palladium in 50ml of toluene was combined with 10 ml of a 2M sodium bicarbonatesolution. This mixture was treated with 1.1 g (9.0 mmol) of the above3-pyridylboronic anhydride, and it was stirred vigorously at 105° C.under nitrogen for 24 hours. The half-complete reaction was charged withan additional 1.0 g of 3-pyridylboronic anhydride and heating wascontinued another 24 hours. The cooled mixture was filtered throughfiltercel. The organic layer was washed with a saturated sodium chloridesolution. The toluene was evaporated and the residue was partitionedbetween 1M hydrochloric acid solution and methylene chloride. Theaqueous layer was basified with 5M sodium hydroxide solution and theproduct was extracted into methylene chloride. After washing with asaturated sodium chloride solution and drying over sodium sulfate themethylene chloride was evaporated leaving a viscous oil. This crudeproduct was chromatographed over a silica gel column using 10% ethylacetate in toluene, then 25% ethyl acetate in toluene, and finally 1:1ethyl acetate/toluene as eluent. The purified(2aR,4S)-1-benzoyl-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indolewas an oil weighing 2.99 g.

C.(2aR,4S)-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A solution of 2.75 g (6.26 mmol) of the above 1-benzoyl compound in 50ml of tetrahydrofuran was stirred at -78° C. as 7.7 ml (11.3 mmol) of a1.47M butyllithium in hexane solution was added. This solution wasallowed to warm to 0° C., then poured into water and extracted withmethylene chloride. The methylene chloride was evaporated and theresidue was chromatographed over 50 g of florisil using ethyl acetate aseluent. The product from the column was a pale yellow oil weighing 2.0 gwhich assayed as title product.

EXAMPLE 23

Preparation of(-)(2aR,4S)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

To a cool (-5° C.) solution of 2.6 g (3.6 mmol) of(-)(2aR,4S)-1-triphenylmethyl-6-(1-oximidoethane)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(prepared substantially in accordance with the oxime substrate preparedin Example 8) in 100 ml of tetrahydrofuran was added 6.9 ml of a 1.6Msolution of n-butyllithium in hexane. The resulting solution was stirredat -5° C. for one hour and then 2 ml (26 mmol) of dimethylformamide wasadded all at once. The resulting solution was warmed to room temperatureand then stirred for one more hour. After stirring at room temperaturefor one hour, the reaction solution was poured into 50 ml of a 1Nsulfuric acid solution. The acidic solution was warmed on a steam bathfor one hour, cooled to room temperature and then extracted with diethylether to remove impurities. The acidic solution was made alkaline withexcess 5N sodium hydroxide solution and then extracted with ethylacetate. The extract was washed with a saturated brine solution, driedover magnesium sulfate and then concentrated in vacuo to provide 1 g ofan oil. This oil was purified by flash chromatography (using ethylacetate as eluent) to provide 400 mg of the title compound as an oil.

EXAMPLE 24

Preparation of(+)(4S)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

A mixture of(+)(2aS,4R)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(180 mg, 0.5 mmol) and 1 g of MnO₂ in 40 mL of CH₂ Cl₂ was sonicated at50-55 KHz for 2 hr. The reaction mixture warmed to reflux during thetime period. The reaction mixture was filtered through a celite pad andthe filtrate was concentrated to dryness in vacuo. The residue waschromatographed (flash column, silica gel, ethyl acetate) to provide 50mg of the isoxazole indole product as an oil.

MS (FD) 323

EXAMPLE 25

Preparation of(-)(4R)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

A mixture of(-)(2aR,4S)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(400 mg, 1.2 mmol) and 1 g of MnO₂ in 100 ml of CH₂ Cl₂ was sonicated at50-55 KHz for four hours. The reaction mixture was warmed to refluxduring the time period. After four hours, the reaction mixture wasfiltered through a celite pad and the filtrate was concentrated todryness in vacuo. The resulting residue was chromatographed (flashcolumn, silica gel, EtOAc) to provide 55 mg of title product as an oil.MS m/e 323(FD)

NMR (300 MHz, CDCl₃) δ 0.90 (t, 6H); 1.2-1.6 (m, 5H); 2.2-3.6 (m, 8H);6.6 (s, 1H); 6.9 (s, 1H); 7.2 (d, 1H); 7.4 (d, 1H); 8.0 (bs, 1H); 8.4(s, 1H).

EXAMPLE 26

Preparation of(-)(4R)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

A mixture of(-)(2aR,4S)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(253 mg, 0.8 mmol) and 1 g of MnO₂ in 100 ml of CH₂ Cl₂ was sonicated at50-55 KHz for four hours. The reaction mixture was warmed to refluxduring the time period. After four hours, the reaction mixture wasfiltered through a celite pad and the filtrate was concentrated todryness in vacuo. The resulting residue was chromatographed (flashcolumn, silica gel, EtOAc) to provide 130 mg of title product.Recrystallization from hexane gave 60 mg of purified title product.

mp 126°-127° C. MS m/e 323 (FD) Analysis calculated for C₂₀ H₂₅ N₃ O:Theory: C, 74.27; H, 7.79; N, 12.99; Found: C, 74.44; H, 7.71; N, 12.78.

EXAMPLE 27

Preparation of(-)(4R)-6-(5-isoxazolyl)-4-[di-(cyclopropylmethyl)amino]-1,3,4,5-tetrahydrobenz-[cd]indole

A mixture of(-)(2aR,4S)-6-(5-isoxazolyl)-4-[di-cyclopropylmethyl)amino]-1,2,2a,3,4,5-hexahydrobenz-[cd]indole(660 mg, 1.9 mmol) and 3 g of MnO₂ in 100 ml of CH₂ Cl₂ was sonicated at50-55 KHz for four hours. The reaction mixture was warmed to refluxduring the time period. After four hours, the reaction mixture wasfiltered through a celite pad and the filtrate was concentrated todryness in vacuo. The resulting residue was chromatographed (flashcolumn, silica gel, EtOAc) to provide 300 mg of title product.Recrystallization from hexane gave 125 mg of purified title product.

mp 146°-147° C. MS m/e 347(FD) [α]_(D) =43.58° (MeOH). Analysiscalculated for C₂₂ H₂₅ N₃ O: Theory: C, 76.05; H, 7.25; N, 12.09; Found:C, 76.09; H, 7.37; N, 12.10.

EXAMPLE 28

Preparation of(-)(4R)-6-(3-pyrazolyl)-4-[di-(cyclopropylmethyl)amino]-1,3,4,5-tetrahydrobenz-[cd]indole

A solution of(-)(4R)-6-acetyl-4-[di-(cyclopropylmethyl)amino]-1,3,4,5-tetrahydro-benz[cd]indole(0.5 g, 1.6 mmol) and 2 ml of tris(dimethylamino)methane in 100 ml oftoluene was refluxed for 16 hours. After 16 hours, the reaction solutionwas concentrated to dryness in vacuo and the resulting residue wasdissolved in 100 ml of ethanol. Two milliters of an 85% hydrazinesolution were added to the ethanolic solution and the resulting reactionmixture was stirred at reflux temperature for 2 hours. After 2 hours,the reaction solution was, again, concentrated to dryness in vacuo. Theresulting residue was then dissolved in 50 ml of 1N hydrochloric acidand the acidic solution was extracted with EtOAc. After extraction withEtOAc the acidic solution was then basicified by adding an excess of aconcentrated NH₄ OH solution. The basic mixture was then extracted withEtOAc. The organic extract was washed with a saturated brine solution,dried over MgSO₄ and concentrated to dryness in vacuo to provide 500 mgof an oil. This oil was purified via chromatography (silica gel, flashcolumn, EtOAc) to provide 400 mg of title compound as an oil.

MS m/e 346(FD) NMR (300 MHz, CDCl₃) δ 0.1 (bs, 4H); 0.5 (m, 4H); 0.95(m, 2H); 1.3 (dd, 1H); 2.6-3.8 (m, 9H); 6.4 (s, 1H); 6.9 (s, 1H); 7.2(d, 1H); 7.3 (d, 1H); 7.6 (s, 1H); 8.2 (bs, 1H).

EXAMPLE 29

Preparation of(-)(4R)-6-(3-pyrazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-tetrahydrobenz[cd]indole

A solution of(-)(4R)-6-acetyl-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole(0.4 g, 1.3 mmol) and 2 ml of tris(dimethylamino)methane in 100 ml oftoluene was refluxed for 16 hours. After that time, the reactionsolution was concentrated to dryness in vacuo and the resulting residuewas dissolved in 100 ml of ethanol. Two milliliters of an 85% hydrazinesolution were added to the ethanolic solution and the resulting reactionmixture was stirred at reflux for 2 hours. After 2 hours, the reactionsolution was concentrated to dryness in vacuo and the resulting residuewas dissolved in 50 ml of 1N hydrochloric acid. The acidic solution wasextracted with EtOAc and then basisified by adding an excess of aconcentrated NH₄ OH solution. The basic mixture was then extracted withEtOAc. The organic extract was washed with a saturated brine solution,dried over MgSO₄ and then concentrated in vacuo to provide an oil. Thisoil was purified by chromatography (silica gel, flash column, EtOAc) toprovide 400 mg of title compound as an oil.

MS m/e 322(FD) NMR (300 MHz CDCl₃) δ 0.9 (t, 6H); 1.5 (m, 4H); 2.4-2.6(m, 4H); 2.8 (dd, 1H); 3.0 (m, 2H); 3.1-3.3 (m, 2H); 6.5 (s, 1H); 6.9(s, 1H); 7.1 (d, 1H); 7.3 (bs, 1H); 7.7 (d, 1H); 8.1 (bs, 1H).

EXAMPLE 30

Preparation of (-)(4R)-6-(3-phenyl-1,2,4-oxadiazol-5-yl)-4-(di-n-propylamino)-1,3,4,5-tetrahvdrobenz-[cd]indole

Magnesium dioxide (200 mg) was added to a solution of (-)(2aR,4S)-6-(3-phenyloxadiazol-5-yl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydroxbenz[cd]indole(40 mg, 0.10 mmol) in 15 ml of hexane. The resulting mixture was thensonicated at 50-55 KHz, while maintaining the reaction solution'stemperature between 25°-35° C., for 135 minutes. After that time thereaction mixture was filtered through celite and the recovered solid waswashed sequentially with hexane and CH₂ Cl₂. The filtrate was combinedwith the organic washes and the resulting solution was washedsequentially with water and a saturated brine solution, dried over Na₂SO₄ and then concentrated in vacuo to give 30 mg of an orange film. Thisfilm was purified by flash chromatography [2:3 ether:hexane (NH₄ OH)] togive 70 mg of title product. This product was purified byrecrystallization from a CH₂ Cl₂ /hexane solvent system to give 50 mg oftitle compound as a light green solid.

mp 154°-155° C. Analysis calculated for C₂₅ H₂₈ N₄ O.0.25 H₂ O: Theory:C, 74.14; H, 7.09; N, 13.83; Found: C, 74.21; H, 7.01; N, 13.58.

EXAMPLE 31

Preparation of(-)(4R)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

A solution of 0.65 g (2.0 mmol) of(-)(2aR,4S)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indolein 30 ml of CH₂ Cl₂ was sonicated (50-55 KHz) in the presence of 2.5 gof MnO₂ for 5 hours. The oxidant was removed by filtration throughcelite. The crude product obtained after filtering and removing thesolvent was chromatographed over 15 g of silica gel using 1:9EtOAc/toluene, then crystallized from isooctane to provide 0.24 g oftitle compound.

mp 73°-74° C. Analysis calculated for C₂₀ H₂₅ N₃ O: Theory: C, 74.27; H,7.79; N, 12.99; Found: C, 73.97; H, 7.84; N, 12.90. NMR (300 MHz, CDCl₃)50.90 (t, 6H); 1.49 (sextet, 4H); 260 (t, 4H); 2.82 (t, 1H); 3.00 m,1H); 3.00 (dd, 1H); 3.26 m, 1H); 3.78 m, 1H); 6.90 (s, 1H); 7.28 (s,1H); 7.73 (s, 1H); 7.22 (d, 1H); 7.86 (d, 1H); 7.97 (s, 1H). MS m/e324(FD) [α]_(D) =-60° (c=1, MeOH)

EXAMPLE 32

Preparation of(-)(4R)-6-(5-oxazolyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

A mixture of(-)(2aR,4S)-6-(5-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole(300 mg, 0.9 mmol) and 0.5 g of MnO₂ in 50 ml of methylene chloride wasstirred at room temperature for 16 hours. The oxidant was removed byfiltration through celite. The crude product obtained after filteringand removing the solvent was purified by flash chromatography, usingethyl acetate as eluent, to provide 100 mg of title compound.Recrystallization from hexane gave 60 mg of pure title compound.

m.p. 161°-162° C. MS (FD) 323 [α]D-64.0° (MeOH) Analysis calculated forC₂₀ H₂₅ N₃ O: Theory: C, 74.27; H, 7.79; N, 12.99; Found: C, 73.99; H,7.82; N, 12.74.

EXAMPLE 33

Preparation of(-)(4R)-6-(3-pyridyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indol

A solution of 1.0 g (2.99 mmol) of (2aR,4S)-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole and 1.0 g (9mmol) of indole in 50 ml of THF was treated at 0° C. with 0.61 g (1.70mmol) of benzeneseleninic anhydride. The resulting solution was allowedto warm to room temperature. After 2 hours the reaction solution wasdiluted with water and the product was extracted into methylenechloride. The methylene chloride was evaporated and the resultingresidue was taken up in aqueous tartaric acid. This acidic solution waswashed with methylene chloride, then basified with 5M sodium hydroxidesolution. The product was extracted into methylene chloride. Afterevaporating the methylene chloride the product was chromatographed over25 g of silica gel using 10% ethyl acetate in toluene followed by 1:1ethyl acetate/toluene as eluent. The material from the column wascrystallized from toluene/hexane to afford 0.53 g of title compound.

m.p. 185°-186° C. MS (FD) 334 [α]D-52.0° (MeOH) NMR (300 MHz, CDCl₃) δ0.88 (t,6H), 1.45 sextet,4H), 2.52 (t,4H), 2.45 (dd,1H), 3.03 (m,3H),3.17 (m, 1H), 6.94 (s,1H), 7.17 (d, 1H), 7.27 (d,1H), 7.38 (dd, 1H),7.77 (d, 1H), 8.01 (s,1H), 8.57 (d,1H), 8.74 (s,1H). Analysis calculatedfor C₂₂ H₂₇ N₃ : Theory: C, 79.24; H, 8.16; N, 12.60; Found: C, 79.07;H, 8.15; N, 12.78.

EXAMPLE 34

Preparation of(4R)-6-[2-(1,3,4-oxadiazolyl)]-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

To a solution of 5.0 g (13.1 mmol) of(4S)-6-iodo-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole in 250ml of acetonitrile was added 3.5 g (37 mmol) of 2-hydroxypyridine, 16.9g (122 mmol) of powdered potassium carbonate, and 0.30 g (0.26 mmol) oftetrakis(triphenylphosphine)palladium. The resultant mixture was heatedat 65° C. under a carbon monoxide atmosphere for 14 hours. The cooledmixture was then treated with 2 ml of hydrazine hydrate and stirred foranother 15 hours. After filtering, the mixture was concentrated in vacuoto provide a residue. This residue was taken up in methylene chlorideand extracted with aqueous tartaric acid solution. The aqueous layer wasbasified with 1M sodium hydroxide solution and the product was extractedinto methylene chloride. Evaporation of solvent in vacuo left an oilysolid which, after thorough washing with a 1:2 mixture of toluene andhexane, afforded 0.60 g of(4R)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxylichydrazide. m.p. 199°-201° C.

A solution of 0.20 g (0.64 mmol) of the above hydrazide in 10 ml oftriethylorthoformate was heated at 150° C. under nitrogen for 15 hours.Most of the excess triethylorthoformate was evaporated in vacuo. Theresulting residue was dissolved in aqueous tartaric acid and washed withmethylene chloride. After basifying the aqueous solution with sodiumcarbonate the product was extracted into methylene chloride. Evaporationof solvent in vacuo left crystalline product which was thenchromatographed over 3 g of silica gel using ethyl acetate as eluent.The product from the column was recrystallized from toluene/hexanegiving 0.16 g of title compound.

m.p. 137°-138.5° C. MS (FD) 324 [α]_(D) -93.0° (MeOH) NMR (300 MHz,DMSO-d₆) δ 0.86 (t,6H), 1.40 (sextet,4H), 2.52 (qt,4H), 2.74 (dd, 1H),2.88 (dd, 1H), 3.00 (dd, 1H), 3.11 (m, 1H), 3.63 (d, 1H), 7.07 (s,1H),7.26 (d, 1H), 7.60 (d, 1H), 9.23 (s,1H). Analysis calculated for C₁₉ H₂₄N₄ O: Theory: C, 70.34; H, 7.46; N, 17.27; Found: C, 70.13; H, 7.33; N,16.98.

EXAMPLE 35

Preparation of(-)(4R)-6-(5-phenyl-1,3,4-oxadiazol-2-yl)-4-(di-n-propylamino)-1,3,4,5-tetrahvdrobenz[cd]indole

A solution of 0.20 g (0.64 mmol) of(4R)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxylichydrazide in 2.0 ml of trimethyl-orthobenzoate was heated at 135° C.under nitrogen for 5 hours. After cooling, the semisolid mixture wasdissolved in methylene chloride and the product was extracted intoaqueous tartaric acid. The aqueous solution was basified with sodiumcarbonate and the product was extracted into methylene chloride.Evaporation of the methylene chloride left crystalline product which wasthen chromatographed over 3 g of silica gel using ethyl acetate aseluent. The product from the column was recrystallized from toluene togive 0.21 g of title compound.

m.p. 215°-216° C. MS (FD) 400 [α]_(D) -23.0° (MeOH) NMR (300 MHz,DMSO-d₆) δ 0.88 (t,6H), 1.41 (sextet,4H), 2.55 (t, 4H), 2.74 (dd, 1H),2.82 (d, 1H), 3.11 (m, 2H), 3.70 (d, 1H), 7.09 (s,1H), 7.30 (d,1H), 7.62(m,3H), 7.77 (d, 1H), 8.08 (m,2H). Analysis calculated for C₂₅ H₂₈ N₄ O:Theory: C, 74.97; H, 7.05; N, 13.99; Found: C, 74.70; H, 7.15; N, 13.89.

EXAMPLE 36

Preparation of(4R)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,3,4,5-tetrahvdrobenz[cd]indole

A.(2aS,4R)-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole

A mixture of 100 g (0.21 mol) of(2aS,4R)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indoleand 1 liter of 1M ethanolic potassium hydroxide was refluxed undernitrogen for 5 hours. The cooled mixture was diluted with two volumes ofwater, and the product was extracted into methylene chloride. Afterdrying the extract over sodium sulfate the solvent was evaporatedleaving 78 g of the debenzoylated product as a light brown oil.

B. (4S)-6-iodo-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

A solution of 78 g (0.20 mol) of the above compound in 1 liter ofmethylene chloride was sonicated (50-55 KHz) in the presence of 100 g ofMnO₂ for 24 hours. The oxidant was removed by filtration throughfilterrel. The crude product obtained after filtering and removing thesolvent was chromatographed over silica gel using 3% ethyl acetate intoluene as eluent. The purified indole was a viscous, amber oil weighing72 g.

C.(4R)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole

A suspension of 11.0 g (55 mmol) of potassium hydride (20% dispersion inoil) in 500 ml of tetrahydrofuran was maintained at 0° C. as 20.0 g(52.4 mmol) of the above compound in a few milliters of tetrahydrofuranwas added. After stirring for 40 minutes, the cold solution was treatedwith 16.0 ml (60.4 mmol) of triisopropylsilyl triflate. Stirring wascontinued for another 2 hours. The mixture was then poured into coldsodium bicarbonate solution and the product was extracted into methylenechloride. The extract was washed with a saturated sodium chloridesolution and then dried over sodium sulfate. Evaporation of solvent invacuo left a brown oil which was chromatographed over silica gel usinghexane followed by toluene as eluent. The silylated product from thecolumn was isolated as a light brown oil weighing 26.4 g.

This oil, along with 25 g (69 mmol) of 2-tributylstannyloxazole, wasdissolved in 500 ml of acetonitrile. The resulting solution was treatedwith 1.0 g of tetrakis(triphenylphosphine)palladium and then refluxedunder nitrogen for 24 hours. Most of the acetonitrile was evaporated invacuo to provide an oil. This oil was taken up in 200 ml of diethylether and washed with a 1% hydrogen peroxide solution. The organic layerwas filtered, washed with a saturated sodium chloride solution and thendried over sodium sulfate. The solvent was evaporated and the residualoil was chromatographed over silica gel using toluene followed by ethylacetate as eluent. The resulting coupled product (24 g) was dissolved in250 ml of tetrahydrofuran. To this solution was added 5 g of boric acid.The solution was then cooled to 0° C. and treated with 75 ml of a 1Mtetrabutylammonium fluoride in tetrahydrofuran solution. After one hourthe solution was diluted with water and the product was extracted intomethylene chloride. The methylene chloride was then evaporated, diethylether was added and the product was extracted into aqueous tartaric acid(10 g in 500 ml). The aqueous solution was basified with 1M sodiumhydroxide solution and the product was extracted into methylenechloride. After washing with a saturated sodium chloride solution anddrying over sodium sulfate the methylene chloride was evaporated and theproduct was chromatographed over silica gel using toluene followed by 5%ethylacetate in toluene as eluent. Trituration of the chromatographedproduct with isooctane afforded 6.30 g of crystalline title product.

m.p. 77°-79° C.

The present compounds of Formula 1 have been found to have selectiveaffinity for the 5HT receptors in the brain with much less affinity forother receptors. Because of their ability to selectively bind to 5-HTreceptors, the compounds of Formula 1 are useful in treating diseasestates which require alteration of 5-HT receptor function, particularly5-HT_(1A), and/or 5HT_(1D) but without the side effects which may beassociated with less selective compounds. This alteration may involvereproducing (an agonist) or inhibiting (an antagonist) the function ofserotonin. These disease states include anxiety, depression, excessivegastric acid secretion, motion sickness, hypertension, nausea andvomiting, sexual dysfunction, cognition, senile dementia, migraine,consumptive disorders such as appetite disorders, alcoholism andsmoking. The foregoing conditions are treated with a pharmaceuticallyeffective amount of a compound of Formula 1 or a pharmaceuticallyacceptable salt thereof.

The term "pharmaceutically effective amount", as used herein, representsan amount of a compound of the invention which is capable of diminishingthe adverse symptoms of the particular disease. The particular dose ofcompound administered according to this invention shall, of course, bedetermined by the particular circumstances surrounding the case,including the compound administered, the route of administration, theparticular condition being treated, and similar considerations. Thecompounds can be administered by a variety of routes including the oral,rectal, transdermal, subcutaneous, intravenous, intramuscular orintranasal routes. A typical single dose for prophylactic treatment,however, will contain from about 0.01 mg/kg to about 50 mg/kg of theactive compound of this invention when administered orally. Preferredoral doses will be about 0.01 to about 3.0 mg/kg, ideally about 0.01 toabout 0.1 mg/kg. When a present compound is given orally it may benecessary to administer the compound more than once each day, forexample about every eight hours. For IV administration by bolus, thedose will be from about 10 μg/kg to about 300 μg/kg, preferably about 20μg/kg to about 50 μg/kg.

The following experiments were conducted to demonstrate the ability ofthe compounds of the Formula 1 to bind to 5-HT receptors. Suchexperiments demonstrate the utility of the compounds of Formula 1 intreating disease states (such as those noted above) which requirealteration of the 5-HT receptor function.

The affinities of certain of the compounds of Formula 1 at the central5-HT_(1A) receptors were determined using a modification of the bindingassay described by Taylor, et al., J. Pharmacol. Exp. Ther., 236,118-125 (1986). Membranes for the binding assay were prepared from maleSprague-Dawley rats (150-250 g). The animals were killed bydecapitation, and the brains were rapidly chilled and dissected toobtain the hippocampi. Membranes from the hippocampi were eitherprepared that day, or the hippocampi were stored frozen (-70° C.) untilthe day of preparation. The membranes were prepared by homogenizing thetissue in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at 22°C.) using a Techmar Tissumizer (setting 65 for 15 seconds), and thehomogenate was centrifuged at 39800 xg for 10 minutes. The resultingpellet was then resuspended in the same buffer, and the centrifugationand resuspension process was repeated three additional times to wash themembranes. Between the second and third washes the resuspended membraneswere incubated for 10 minutes at 37° C. to facilitate the removal ofendogenous ligands. The final pellet was resuspended in 67 mM Tris-HCl,pH 7.4, to a concentration of 2 mg of tissue original wet weight/200 μl.This homogenate was stored frozen (-70° C.) until the day of the bindingassay. Each tube for the binding assay had a final volume of 800 μl andcontained the following: Tris-HCl (50 mM), pargyline (10 μM), CaCl₂ (³mM), [³ H]8-OH-DPAT (1.0 nM), appropriate dilutions of the drugs ofinterest, and membrane resuspension equivalent to 2 mg of originaltissue wet weight, for a final pH of 7.4. The assay tubes were incubatedfor 10 minutes at 37° C., and the contents were then rapidly filteredthrough GF/B filters (pretreated with 0.5% polyethylenimine), followedby four 1 ml washes with ice-cold buffer. The radioactivity trapped bythe filters was quantitated by liquid scintillation spectometry, andspecific [³ H]8-OH-DPAT binding to the 5-HT_(1A) sites was defined asthe difference between [³ H]8-OH-DPAT bound in the presence and absenceof 10 μM 5-HT.

The results of the evaluation of various compounds of Formula 1 in thetest system described above are set forth in Table 1, below. In Table 1,the first column provides the example number of the compound evaluatedwhile the second column provides the amount of test compound (expressedin nanomolar concentration) required to inhibit the binding of [³H]8-OH-DPAT by 50% (indicated as IC₅₀).

                  TABLE 1                                                         ______________________________________                                        IN VITRO BINDING AT THE 5-HT1A RECEPTOR                                                      5-HT1A in vitro                                                EXAMPLE NO.    binding (IC.sub.50, nM)                                        ______________________________________                                        24             0.61                                                           26             0.10                                                           30             7.1                                                            31             2.77                                                           32             0.53                                                           33             0.87                                                           34             0.75                                                           35             19.04                                                          ______________________________________                                    

The affinities of certain of the compounds of Formula 1 at the central5-HT_(1D) binding sites were determined using a modification of thebinding assay described by Heuring and Peroutka, J. Neurosci., 7, 894(1987). Bovine brains were obtained and the caudate nuclei weredissected out and frozen at -70° C until the time that the membraneswere prepared for the binding assays. At that time the tissues werehomogenized in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at22° C.) with a Techmar Tissumizer (setting 65 for 15 seconds), and thehomogenate was centrifuged at 39,800 xg for 10 minutes. The resultingpellet was then resuspended in the same buffer, and the centrifugationand resuspension process was repeated three additional times to wash themembranes. Between the second and third washes the resuspended membraneswere incubated for 10 minutes at 37° C. to facilitate the removal ofendogenous 5-HT. The final pellet was resuspended in Tris buffer to aconcentration of 25 mg of original tissue wet weight/ml for use in thebinding assay. Each tube for the binding assay had a final volume of 800μl and contained the following: Tris-HCl (50 mM), pargyline (10 JIM),ascorbate (5.7 mM), CaCl₂ (3 mM), 8-OH-DPAT (100 nM to mask 5-HT_(1A)receptors), mesulergine (100 nM to mask 5-HT_(1C) receptors), [³ H]5-HT(1.7-1.9 nM), appropriate dilutions of the drugs of interest, andmembrane resuspension equivalent to 5 mg of original tissue wet weight,for a final pH of 7.4. The assay tubes were incubated for 10 minutes at37° C., and the contents were then rapidly filtered through GF/B filters(pretreated with 0.5% polyethylenimine), followed by four 1 ml washeswith ice-cold buffer. The radioactivity trapped by the filters wasquantitated by liquid scintillation spectrometry, and specific [3H]5-HTbinding to the 5-HT_(1D) sites was defined as the difference between [³H]5-HT bound in the presence and absence of 10 μm 5-HT.

The results of the evaluation of various compounds of Formula 1 in thetest system described above are set forth in Table 2 below. In Table 2,the first column provides the example number of the compound evaluatedwhile the second column provides the amount of test compound (expressedin nanomolar concentration) required to inhibit the binding of [³ H]5-HTby 50% (indicated as IC₅₀).

                  TABLE 2                                                         ______________________________________                                        In Vitro Binding Activity At The 5-HT1D Receptor                                             5-HT1D in vitro                                                EXAMPLE NO.    binding (IC.sub.50, nM)                                        ______________________________________                                        24             18.60                                                          26             46.36                                                          31             280                                                            32             74.45                                                          33             29.4                                                           34             577                                                            ______________________________________                                    

In another experiment certain compounds of Formula 1 were evaluated todetermine ability to affect serotonin turnover in vivo. As a measure ofsuch affect on serotonin turnover, the decrease of the serotoninmetabolite 5-hydroxyindole acetic acid (5HIAA) was measured. Thefollowing protocol was employed.

Male albino rats were injected either subcutaneously or orally with anaqueous solution of the compound tested. The DH of the solution wasadjusted as necessary to solubilize the compound. A control of thesolution without the test compound was similarly administered to acontrol animal. The rats were decapitated one hour later. The wholebrain was then removed and frozen on dry ice for storage prior toanalysis. 5-Hydroxyindole acetic acid (5HIAA) concentration in wholebrain was measured by liquid chromatography with electrochemicaldetection as reported by Fuller and Perry, "Effects of Buspirone and itsMetabolite, 1-(2-pyrimidinyl)piperazine, on Brain Monoamines and TheirMetabolites in Rats", J. Pharmacol. Exp. Ther., 248, p. 50-56 (1989),incorporated herein by reference. The results of this procedure areprovided in Table III.

In Table III, Column 1 provides the Example No. of the compound testedwhile Column 2 provides the minimum effective dose (in mg/kg) requiredto produce a statistically significant decrease in 5HIAA concentrationrelative to control (generally a 15-20% decrease) for both oral andsubcutaneous methods of administration.

                  TABLE III                                                       ______________________________________                                        Effect On Serotonin Turnover In Vivo                                                         Minimum Effective                                                             Dose (mg/kg)                                                   EXAMPLE NO.      s.c.     p.o.                                                ______________________________________                                        31               1.0      1.0                                                 33               0.3      >10                                                 34               0.1      10                                                  35               >1.0                                                         ______________________________________                                    

The compounds of the present invention are preferably formulated priorto administration. Therefore, yet another embodiment of the presentinvention is a pharmaceutical formulation comprising a compound of theinvention and a pharmaceutically acceptable excipient therefor.

The present pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be mixed with an excipient, diluted by an excipient or enclosedwithin an excipient serving as a carrier which can be in the form of acapsule, sachet, paper or other container. When the excipient serves asa diluent, it can be a solid, semi-solid or liquid material which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include lubricating agents such as talc,magnesium stearate and mineral oil, wetting agents, emulsifying andsuspending agents, preserving agents such as methyl andpropylhydroxybenzoates, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.5 to about 50 mg, more usually about 1 toabout 10 mg of the active ingredient. The term "unit dosage form" refersto physically discrete units suitable as unitary dosages for humansubjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                           Quantity (mg/capsule)                                      ______________________________________                                        (-)-6-(2-oxazolyl)-4-(di-n-                                                                        25                                                       propylamino)-1,3,4,5-tetrahydrobenz-                                          [cd]indole                                                                    Starch, dried        425                                                      Magnesium stearate   10                                                       Total                460       mg                                             ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

A tablet formula is prepared using the ingredients below:

    ______________________________________                                                          Quantity (mg/tablet)                                        ______________________________________                                        (±)-6-[3-(5-aminothiazolyl)]-4-                                                                25                                                        (di-n-propylamino)-1,3,4,5-tetra-                                             hydrobenz[cd]indole                                                           Cellulose, microcrystalline                                                                       625                                                       Colloidal silicon dioxide                                                                         10                                                        Stearic acid        5                                                         ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

    ______________________________________                                                            Weight %                                                  ______________________________________                                        (±)-6-(5-isoxazolyl)-4-(di-n-                                                                    5                                                       propylamino)-1,3,4,5-tetrahydrobenz-                                          [cd]indole                                                                    Lactose               95                                                      ______________________________________                                    

The active compound is mixed with the lactose and the mixture added to adry powder inhaling applicance.

Formulation 4

Tablets each containing 60 mg of active ingredient are made up asfollows:

    ______________________________________                                        (+)-6-(2-pyrazolyl)-4-(di-n-                                                                         60       mg                                            propylamino)-1,3,4,5-tetrahydrobenz-                                          [cd]indole                                                                    Starch                 45       mg                                            Microcrystalline cellulose                                                                           35       mg                                            Polyvinylpyrrolidone (as 10%                                                                         4        mg                                            solution in water)                                                            Sodium carboxymethyl starch                                                                          4.5      mg                                            Magnesium stearate     0.5      mg                                            Talc                   1        mg                                            Total                  150      mg                                            ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 4 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 16 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

Formulation 5

Capsules each containing 20 mg of medicament are made as follows:

    ______________________________________                                        (±)-6-(5-oxadiazolyl)-4-(di-                                                                      20       mg                                            methylamino)-1,3,4,5-tetrahydrobenz-                                          [cd]indole                                                                    Starch                 169      mg                                            Magnesium stearate     1        mg                                            Total                  190      mg                                            ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 190 mg quantities.

Formulation 6

Suppositories each containing 225 mg of active ingredient are made asfollows:

    ______________________________________                                        (+)-6-(4-pyridyl)-4-(di-n-propyl-                                                                   225       mg                                            amino)-1,3,4,5-tetrahydrobenz[cd]-                                            indole                                                                        Saturated fatty acid glycerides to                                                                  2,000     mg                                            ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions each containing 50 mg of medicament per 5 ml dose are madeas follows:

    ______________________________________                                        (±)-6-(2-thiazolyl)-4-(di-n-                                                                      50        mg                                           propylamino)-1,3,4,5-tetrahydrobenz-                                          [cd]indole                                                                    Xanthan gum            4         mg                                           Sodium carboxymethyl cellulose (11%)                                          Microcrystalline cellulose (89%)                                                                     50        mg                                           Sucrose                1.75      g                                            Sodium benzoate        10        mg                                           Flavor                 q.v.                                                   Color                  q.v.                                                   Purified water to      5         ml                                           ______________________________________                                    

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethylcellulose inwater. The sodium benzoate, flavor and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

Formulation 8

Capsules each containing 50 mg of medicament are made as follows:

    ______________________________________                                        (+)-6-(5-isoxazolyl)-4-(dimethyl-                                                                   50        mg                                            amino)-1,3,4,5-tetrahydrobenz[cd]-                                            indole                                                                        Starch                507       mg                                            Magnesium stearate    3         mg                                            Total                 560       mg                                            ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules.

We claim:
 1. A compound of the formula ##STR15## wherein: R¹ ishydrogen, C₁ -C₄ alkyl, C₃ -C₄ alkenyl, cyclopropylmethyl, phenyl (C₁-C₄ alkyl), naphthyl (C₁ -C₄ alkyl), phenyl (C₁ -C₄ alkyl) substitutedwith one or two substituents selected from the group consisting of C₁-C₃ alkoxy, halo, hydroxy, C₁ -C₃ thioalkyl, nitro, C₁ -C₃ alkyl ortrifluoromethyl, naphthyl (C₁ -C₄ alkyl) substituted with one or twosubstituents selected from the group consisting of C₁ -C₃ alkoxy, halo,hydroxy, C₁ -C₃ thioalkyl, nitro, C₁ -C₃ alkyl or trifluoromethyl,--(CH₂)_(n) S(C₁ -C₄ alkyl), --C(O)R⁴, or --(CH₂)_(n) C(O)NR⁵ R⁶ ;R² ishydrogen, C₁ -C₄ alkyl, cyclopropylmethyl or C₃ -C₄ alkenyl; R³ ishydrogen, C₁ -C₄ alkyl or an amino blocking group; n is 1-4; R⁴ ishydrogen, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy or phenyl; R⁵and R⁶ are independently hydrogen, C₁ -C₄ alkyl, or C₅ -C₈ cycloalkylwith the proviso that when one of R⁵ or R⁶ is a cycloalkyl the other ishydrogen; HET is a heterocyclic ring selected from the group consistingof ##STR16## where R is hydrogen, C₁ -C₃ alkyl, halogen, hydroxy, C₁ -C₃alkoxy, C₁ -C₃ thioalkyl, NH₂, CN or phenyl; or pharmaceuticallyacceptable salts thereof.
 2. The compounds of claim 1 wherein R¹ and R²are independently C₁ -C₃ alkyl or a pharmaceutically acceptable saltthereof.
 3. The compounds of claim 1 wherein R³ is hydrogen or apharmaceutically acceptable salt thereof.
 4. The compounds of claim 2wherein R³ is hydrogen or a pharmaceutically acceptable salt thereof. 5.The compounds of claim 1 wherein R¹ is --(CH₂)_(n) C(O)NR⁵ R⁶ wherein nis 2, R⁵ is hydrogen, R⁶ is cyclohexyl, R² is C₁ -C₃ alkyl, and R³ ishydrogen or C₁ -C₄ alkyl or a pharmaceutically acceptable salt thereof.6. A substantially pure stereoisomer of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 7. A substantially purestereoisomer of a compound of claim 6, or a pharmaceutically acceptablesalt thereof, wherein the stereoisomer has R configuration at the4-position.
 8. A pharmaceutical formulation comprising a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof in combination with a pharmaceuticallyacceptable excipient therefor.
 9. A method for treating a mammal with aserotonin-related disorder selected from the group consisting ofanxiety, depression, excessive gastric acid secretion, hypertension,nausea and vomiting, motion sickness, senile dementia, appetitedisorders, alcoholism and smoking which comprises administering to saidmammal an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 10. A compound of claim 1selected from the group consisting of(-)(4R)-6-(3-phenyl-1,2,4-oxadiazol-5-yl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole;(4R)-6-[2-(1,3,4-oxadiazolyl)]-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole;(-)(4R)-6-(5-phenyl-1,3,4-oxadiazol-2-yl)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole,or a pharmaceutically acceptable salt thereof.